The Latest Developments in Immunomodulation of Mesenchymal Stem Cells in the Treatment of Intrauterine Adhesions, Both Allogeneic and Autologous

Abstract

Intrauterine adhesion (IUA) is an endometrial fibrosis disease caused by repeated operations of the uterus and is a common cause of female infertility. In recent years, treatment using mesenchymal stem cells (MSCs) has been proposed by many researchers and is now widely used in clinics because of the low immunogenicity of MSCs. It is believed that allogeneic MSCs can be used to treat IUA because MSCs express only low levels of MHC class I molecules and no MHC class II or co-stimulatory molecules. However, many scholars still believe that the use of allogeneic MSCs to treat IUA may lead to immune rejection. Compared with allogeneic MSCs, autologous MSCs are safer, more ethical, and can better adapt to the body. Here, we review recently published articles on the immunomodulation of allogeneic and autologous MSCs in IUA therapy, with the aim of proving that the use of autologous MSCs can reduce the possibility of immune rejection in the treatment of IUAs.

Introduction

Intrauterine adhesion (IUA), also known as Asherman syndrome, is condition involving endometrial fibrosis caused by damage to the basal layer of the uterus, leading to partial or full adhesion of the uterine cavity (1, 2). IUA is usually accompanied by decreased menstrual flow, and in severe cases, secondary amenorrhea. Moreover, IUA affects embryo implantation and development as a result of reduction or even complete disappearance of intrauterine volume, leading to female infertility and recurrent miscarriage (3). However, normal endometrium is not scarred during repair. Under the influence of uterine manipulation and inflammatory cytokines, the endometrium participates in hypoxia, reduces new blood vessels, and controls the expression of adhesion-related cytokines (4).

At present, hysteroscopic endometrial adhesion decomposition combined with various methods, such as insertion of an intrauterine balloon (5), administration of hyaluronic acid gel (6) and polyethylene oxide-sodium carboxymethylcellulose gel (2), etc., can be used to treat IUA. However, the common adhesion release can only improve the problem of uterine cavity stenosis and cannot completely reverse endometrial fibrosis. Therefore, researchers have proposed the use of ​​ stem cells to treat IUA because of their regenerative ability (7).

Recently, Cao et al. (8) reported that the use of umbilical cord MSCs in allogeneic cell therapy could improve the treatment of recurrent uterine adhesions, and subsequently conducted a phase I clinical trial. Since umbilical cord MSCs have low immunogenicity and low tumorigenicity, they have great advantages in the application of IUA. On the one hand, clinical trials showed that endometrial thickening and IUA score after treatment were lower than those before treatment. On the other hand, DNA short tandem repeat (STR) analysis showed the regenerated endometrium only containing patient DNA, so that umbilical cord MSCs exhibit good safety. Mare (9) also confirmed that allogeneic MSCs can regulate the protein pattern and increase the proliferation of glandular epithelial cells, thereby exerting an anti-scarring effect. Although the immunogenicity of MSCs is lower than that of other stem cells, immune rejection of allogeneic MSCs can still occur. Ankrum et al. (10) pointed out that antibodies and immune rejection may be produced during the treatment of allogeneic donor MSCs. In other words, MSCs may not have immune privileges.

Currently, the mechanism by which allogeneic mesenchymal stem cells induce immune rejection remains unclear. Most researchers believe that the human leukocyte antigen (HLA) of allogeneic MSCs does not match the receptor type (11). Others have suggested that immune rejection caused by allogeneic MSCs is also related to immune cells (12), immunoactive substances (3, 13) and immune organs (14). Currently, there is no good method to control immune rejection. A prior study suggested (10) that the immune persistence of MSCs could be improved, and immune tolerance could be enhanced. More importantly, others have suggested (11) that knockout of beta-2 microglobulin could be performed to enhance repair. The most direct approach is the use of autologous MSCs. Kim et al. believe (15) that the combination of MSC spheres and autologous composite sheets could be used to avoid immune rejection and improve the effectiveness of stem cell therapy. This article reviews the comparison between allogeneic and autologous MSCs. In addition, we will summarize the mechanism by which allogeneic mesenchymal stem cell therapy induces immunoregulation. Furthermore, we will discuss the therapeutic prospects of autologous MSCs.

Intrauterine Adhesion

IUA often progresses as a consequence of uterine cavity operation. Deans et al. conducted (16) a retrospective analysis of 1856 patients with intrauterine adhesions and found that 67% of curettage was induced or spontaneous, while 22% was due to postpartum bleeding. Christina et al. (17) considered that antagonistic effects occur due to increased prolactin levels and decreased estrogen levels in the postpartum period; therefore, the endometrium is more prone to atrophy. Additionally, IUA is associated with inflammatory cytokines. The experimental results of Mo et al. (18) demonstrated that preoperative inflammation in IUA patients was significantly higher than that in non-IUA patients. At present, the only confirmed infectious factor that causes IUA is genital tuberculosis (4). Research has shown (19) that Mycobacterium tuberculosis infection of the uterine cavity can lead to focal ulceration, necrosis, or bleeding of the endometrial tissue, while destruction of the endometrium can cause partial or complete IUA. Another important reason is the insufficient endometrial blood perfusion (20). For example, uterine artery embolism, B-Lynch suture, hysteroscopic myomectomy, etc. (21). Due to the long-term insufficient blood supply to the endometrium, it is difficult to regenerate, which increases the possibility of IUA (Figure 1).

Figure 1

At present, the immune mechanism of intrauterine adhesions is not clear, Zhao et al. (22) believe that it is related to the imbalance of vaginal flora and microecology. The causes of microecological imbalance may be related to the long-term use of antibiotics, frequent sexual intercourse, vaginal flushing, and decreased estrogen. These factors greatly increase the incidence of uterine inflammation. When the endometrium is normal, it can resist the invasion of these inflammatory cytokines. However, once the endometrium is damaged due to uterine operation, the surface barrier is destroyed. On the one hand, bacteria invade the endometrium, causing local inflammatory reactions, and the pro-inflammatory cytokines IL-6 and IFN-γ increase. Negative feedback reduced the activity of matrix metalloproteinase (MMP) and promoted the generation of endometrial fibrosis. On the other hand, damaged epithelial cells (23) release IL-25, IL-33, TSLP, other cells can directly or indirectly promote Th2 immune response to promote fibrosis. What’s more, NF-κB (24) transcription cytokine promotes the expression of intrauterine adhesion inflammatory cytokines and plays a central role in inflammatory diseases. It also closely intersects with the pathogenic cytokines of intrauterine adhesion such as TGF-β, TNF-α, IL-1 and IL-18. Wang et al. (25) found that the expression of NF-κB in endometrium from patients with endometrial adhesion was significantly higher than that in normal endometrium (Figure 2).

Figure 2

Currently, the commonly used clinical treatment method is transcervical resection of adhesions (TCRA). To improve the efficacy of the IUA, an intrauterine contraceptive device and intrauterine balloon can be inserted first (26). Intrauterine devices and balloons can expand the narrow uterine cavity to improve the long-term prognosis of patients. In addition, we can also increase biological barriers, such as new cross-linked hyaluronan gel (27), auto-cross-linked hyaluronan gel (28), and estrogen gel (29). However, the prognosis of IUA is still not ideal. Some researchers have postulated (21) that the degree of recurrence of IUA is related to the degree of adhesion. In addition, Hanstede et al. (30) compared the degree of IUA and the recurrence rate of patients with hysteroscopic adhesiolysis. The results indicated that the recurrence rate of first-degree IUA was 3.8% (n=24), that of second-degree IUA was 33.1% (n=211), and that of third-degree IUA was 35.4% (n=226).

Furthermore, the release of adhesions also needs to promote the regeneration and repair of endometrial fibrosis. Due to the regenerative ability of stem cells, researchers are considering the use of stem cells for treatment. Studies have shown (31) that collagen scaffolds loaded with human umbilical cord mesenchymal stem cells can promote endometrial structural reconstruction and functional recovery (Table 1).

Mesenchymal Stem Cells

Background of Mesenchymal Stem Cells

Mesenchymal stem cells (MSCs) are pluripotent stem cells which can attach to the wall where they grow and replicate (35). The sources of MSCs are relatively abundant; for example, they can be extracted from the bone marrow, umbilical cord, adipose tissue, peripheral blood, and so on (36). MSCs have become a research hotspot for their diverse functions, which include cell differentiation and proliferation, regulation of inflammatory processes, control of oxidative stress, and angiogenesis (37).

Types of Mesenchymal Stem Cells

Currently, there are several classifications of MSCs; donor MSCs can be classified as either allogeneic or autologous. Allogeneic MSCs are derived from other donors for implantation into the recipient patient. Because they are extracted from a foreign body, the number of allogeneic MSCs can be quite large. However, since allogeneic MSCs are equivalent to foreign matter, they are not ethically recognized in humans (38). In contrast, autologous MSCs are cells that are extracted from the patient’s own tissues, induced and differentiated, and then re-implanted for treatment. Therefore, they adapt better to the patient’s body, and are less likely to suffer from immune rejection. In the past decade (39), genetic modification of autologous hematopoietic stem cells has been used for the treatment of single-gene diseases. Moreover, they are more in line with people’s ethical requirements and are recognized by more people. At present, autologous MSCs have been used to treat several diseases, including multiple sclerosis (40), post-burn scar treatment (41), refractory rectovaginal Crohn’s fistulas (42), and patients with advanced tumors (43), among others (Table 2).

In addition, MSCs can be classified by source, as either dental pulp MSCs (44), human umbilical cord MSCs (45), bone marrow MSCs (46), and adipose tissue-derived MSCs (47). In addition, if they are classified by developmental potency, they can be divided into totipotent stem cells (TSCs), pluripotent stem cells, and unipotent stem cells.

Characteristics of MSCs

MSCs have many notable characteristics. First, MSCs cannot differentiate and self-renew (52). Hsiao et al. (53) proposed that treatment with undifferentiated MSCs can improve insulin resistance in diabetic rats, rebalance inflammation, and improve blood sugar levels. Regarding the differentiation ability of MSCs, researchers have suggested that MSCs can differentiate into adipocytes, osteoblasts, and chondrocytes. In addition, detection of MSC surface antigens indicated that the expression of markers such as CD166, CD44, CD29, CD73, CD90, and CD105 increased significantly with the increase of transmission algebra (20). Moreover, MSCs also express CD11, CD14, CD45, and CD34. However, as the transmission algebra increases, these markers are reduced or lost. Therefore, MSCs can be detected using the above-mentioned markers.

Mechanism and Application of MSCs in the Treatment of IUA

MSC Immunization

Current research indicates that application of bone marrow MSCs can promote endometrial regeneration by suppressing the innate and adaptive immune systems (54). On the one hand, in the innate immune system, MSCs can inhibit the activation, proliferation and cytotoxicity of natural killer cells (NK cells) (55). Conversely, in adaptive immunity, MSCs (56) can inhibit the proliferation of B and T cells, and further prevent the proliferation and differentiation of T cells into pro-inflammatory TH1 and TH17 helper T cells. In addition, MSCs can promote the differentiation of T cells into tolerant Treg cells (57), and can regulate the action of monocytes, dendritic cells, and NK cells by secreting chemokines (58), such as IGF-1, TGF-β, bFGF, HGF, IL-6, SDF-1, M-CSF, VEGF, PIGF, and MCP-1 (55).

Toll-like receptors (TLR) are also involved in the immunotherapy of MSCs. When faced with a danger signal, TLRs recognize danger signals and are activated to trigger a cellular response, mobilizing innate and adaptive immune cells (59). The results showed that MSCs combined with TLR4 promoted the secretion of pro-inflammatory cytokines. In contrast, if combined with TLR3, MSCs promote the secretion of anti-inflammatory cytokines (60). When microorganisms are infected, exogenous danger signals such as endotoxins or lipopolysaccharides (LPS) disappear. Meanwhile, abnormal or damaged cells overflow into the circulatory system, resulting in the expression of heat shock proteins, an endogenous danger signal. Get rid of the “danger signal” to activate the sentinel innate immune cells (for example, dendritic cells) TLR. Various immune cells are recruited to the site of endometrial damage (61).

Moreover, researchers have found that the concentration of macrophages in the endometrium of patients with IUA decreased, which may be related to a decrease in CSF-1 (62). Otherwise, another study indicated (63) that transplantation of Human amniotic epithelial cells (HAECs) can be performed through autophagy-induced recovery of damaged endometrium. VEGF expression in the menstrual and proliferative phases can promote the reconstruction of endometrial tissue. HAECs can increase the expression of VEGF, promote angiogenesis, and promote the recovery of endometrial fibrosis.

Differentiation Therapy of MSCs

Mesenchymal stem cells have the capability to differentiate After MSCs reach the tissue, they secrete stem cell cytokines such as SCF and M-CSF to reactivate the differentiation potential of the endogenous stem cells of the damaged tissue, thus promoting the generation of new tissue cells to replace damaged cells, resulting in tissue recovery; this is termed stem cell differentiation therapy (64). At present, MSC differentiation has been applied in various fields. A set of clinical treatment data of Ashman syndrome showed (65) that patients receiving autologous CD9 ⁺, CD44 ⁺, CD90 ⁺ bone marrow MSC transplantation experienced improved endometrial vascularization and an increase in endometrial thickness. One such patient subsequently underwent in vitro fertilization and embryo transfer, and successfully carried a fetus to term.

Differentiation therapy of MSCs can also be applied to other aspects, such as the treatment of Parkinson’s disease, in which EDSCs are promoted to differentiate into dopamine-producing cells (66). Studies have shown (67) that CD90, CD146, and PDGFR-β in HEDSCs can differentiate into neuron-like cells. Moreover, they can also differentiate into cholinergic neuron-like cells (68), oligodendrocyte-like cells (69), insulin-producing cells (70), cardiomyocyte-like cells (71), megakaryocyte-like cells (72), and urothelial cells (73).

Stem Cell Paracrine Therapy

MSCs coordinate tissue recovery by releasing soluble paracrine cytokines (74). Treatment of IUA through the paracrine pathway is currently the most popular research method as IUA is partially affected by inflammatory cytokines. One of the subgroups of inflammatory cytokines is IL-1ra in the acute inflammatory paracrine effect of MSCs. IL-1ra inhibits cytokine stimulation of the helper T lymphocyte system, as well as the production of the inflammatory cytokines TNF-α in macrophages in an IL-1ra-dependent manner (74).

Furthermore, because exosomes can make mesenchymal stem cells specialize in the treatment of certain diseases, they are now an active field. Exosomes are small, single-membrane secretory organelles with a diameter of 30–200 nm (75). Recent studies have shown (76) that the function, targeting, and mechanism-driven accumulation of specific cellular components in exosomes indicate that they play a role in regulating intercellular communication.

At present, exosomes are also used in the IUA. Yao et al. (77) demonstrated that exosomes from MSCs can reverse the epithelial to mesenchymal transition (EMT) through action of the TGF-β1/Smad pathway and promote the repair of damaged endometrium in 64 female rabbits. Liao et al. (78) also summarized the manner by which different exosomes could be used to treat female reproductive disorders, and concluded that MSCs can improve female fertility in in vitro and in vivo models. Therapeutic mechanisms include angiogenesis, immune regulation, anti-fibrosis, and anti-oxidative stress. In addition, after subcutaneous injection of a mixture of matrix gel and MSCs in mice, the number of hemoglobin or CD31⁺ cells increased, indicating that MSCs can promote the formation of functional capillaries (79). Furthermore, Zhao et al. (80) demonstrated that ADSC-ex promotes endometrial regeneration and fertility recovery. Moreover, Tao et al. (81) found through experiments that Mir-29a in bone marrow MSC exosomes can inhibit fibrosis in the process of endometrial adhesion repair.

Homing Characteristics of Stem Cells

The homing function of stem cells functions to recruit stem cells by disrupting the tissue-secreted chemokine system (82). It is well known that chemokine SDF1 and its special receptor CXCR4 play a key role in the homing of BMSCs (83). Moreover, studies have shown that ERα promotes the proliferation and migration of BMSCs through SDF1/CXCR4 (84). Furthermore, the CXCL12/CXCR4 protein ligand is a chemokine receptor complex that can transmit stem cells to the uterus (85), and thus promote endometrial repair. In addition, G-CSF has been shown to mobilize hematopoietic stem cells from the bone marrow into the blood, thereby reducing migration to the endometrium (86). G-CSF can also enhance the expression of cytokeratin, vimentin, integrin, and leukemia inhibitory cytokine (LIF) and regulate endometrial function (7).

Immunoregulation of Allogeneic MSCs

It is well known that the immunoregulation and regeneration characteristics of MSCs are the reason why they are used to treat many diseases. Because bone marrow MSCs are considered to have low immunogenicity, their implantation does not trigger histocompatibility disorders or predict possible immune rejection (87). The low immunity of MSCs is due to the lack of expression of major histocompatibility complex II (MHCII) and the low expression of costimulatory molecules such as MHCI, CD80, and CD86 (88).

Studies have shown that under certain conditions, bone marrow MSCs can secrete proinflammatory cytokines and act as antigen-presenting cells to promote immune responses (89). Bone marrow MSCs can effectively reduce phagocytosis and antigen presentation of monocytes/macrophages, and promote the expression of immunosuppressive molecules such as interleukin IL-10 and programmed cell death 1 ligand 1 in these cells (90). In addition, they can effectively inhibit the maturation of dendritic cells and their ability to produce pro-inflammatory cytokines, in addition to stimulating strong T-cell responses (90). Furthermore, MSCs can inhibit the generation and pro-inflammatory properties of CD4 ⁺ T helper cells 1 (Th₁) and Th₁₇ cells, and promotes the proliferation and inhibition of regulatory T cells. Bone marrow MSCs can also damage the expansion, cytokine secretion, and cytotoxic activity of pro-inflammatory CD8 ⁺ T cells (90).

Allogeneic MSCs and Monocytes/Macrophages

Immunomodulatory macrophages can be categorized as either pro-inflammatory M₁ and anti-inflammatory M₂ macrophages (91). Some scholars have pointed out that MSCs can effectively promote the polarization of macrophages into the M₂ type. This process is mediated by a variety of soluble molecules, including PGE2, IDO, HGF, IL-1RA, TSG6, TGF-β, etc. (90). In addition, MSCs induce M2 polarization, the anti-inflammatory cytokines IL-10, arginase-1, and TGF-β increase, and the pro-inflammatory cytokines TNF-α, IL-12, and IL-1 decrease, inhibit T cell response, and induce the production of regulatory T cells. Finally, this leads to further immunosuppression, which is conducive to the treatment of allogeneic MSCs (92).

Furthermore, when human umbilical cord-derived MSCs (UC-MSCs) are co-cultured with monocytes and macrophages, the expression of HLA-DR/DP/DQ and CD86 is reduced, and the phagocytosis and antigen presentation ability of monocytes and macrophages is decreased (93). This indicates that, compared with ordinary stem cells, UC-MSCs can reduce the chance immune rejection caused by allogeneic transplantation. In addition, US-MSCs can induce CD14+, CD16+, and CD206+ in mice after being phagocytosed by monocytes, leading to an increase in the anti-inflammatory cytokines IL-10 and PD-L1 (94) (Figure 3).

Figure 3

Allogeneic MSCs and Dendritic Cells

Dendritic cells (DCs) are antigen-presenting cells that can induce T cells to produce an immune response. MSCs can inhibit the maturation of dendritic cells by regulating the expression of HLA-DR, CD40, OX40L, CD80, and CD83 (95), and upregulating the expression of PD-L1 (96), thereby reducing its ability to activate T cells. In addition, when DCs are co-cultured with MSCs, the pro-inflammatory cytokines secreted by CD1c+ DCs are reduced, and the anti-inflammatory cytokine IL-10 secreted by plasmacytoid DCs is increased (97). Moreover, studies have shown that exosomes released by adipose-derived mesenchymal stem cells can inhibit IL-6 and increase the expression of the anti-inflammatory cytokines IL-10 and TGF-β (98). Furthermore, treatment of mouse dendritic cells with MSC-derived exosomes did not stimulate T cell proliferation after LPS activation (98)

Allogeneic MSCs and T Cells

In the T cell family, CD4 ⁺ helper T cells and CD8 ⁺ cytotoxic T cells play important roles in the immune regulation of MSCs. On the one hand, CD4 ⁺ T cells can bind to CD40 and CD40 ligands on their cell surface, thereby enhancing the ability of dendritic cells to induce CTL. On the other hand, CD40 can maintain CTL activity by triggering the secretion of IL-2 (99). However, MSCs inhibit the proliferation of these two tesla cells through paracrine and cell contact, thereby reducing the release of the pro-inflammatory cytokines TNF-α and IFN-γ, and reducing the immune rejection between allogeneic MSC receptors (100).

In addition, exosomes extracted from mouse MSCs can inhibit T cell proliferation by upregulating cyclin-dependent kinase inhibitor 1 B and downregulating cyclin-dependent kinase 2 (101). Bone marrow mesenchymal stem cells can transform Th1 to Th2 mediated by dendritic cells and induce Tregs (56), reduce pro-inflammatory cytokines IFN-α, IL-17, and IL-6, and increase the anti-inflammatory cytokines IL-4 and IL-10 (102). Moreover, exosomes extracted from umbilical cord-derived mesenchymal stem cells can inhibit CD8 + T cells and Th1 cells, reduce the secretion of pro-inflammatory cytokines IFN-γ and TNF-α, induce Tregs, and promote the secretion of the anti-inflammatory cytokines IL-10 (103) (Figure 4).

Figure 4

Immune Rejection Reaction Between Allogeneic and Autologous Mesenchymal Stem Cells

Chronic rejection is the most serious major adverse reaction after allogeneic transplantation, and is also the main obstacle affecting patient survival (104). Due to the presence of alloreactive T cells in the allograft, the allograft recipient usually experiences an acute graft-versus-host response (GVHR) (105–108). Possible mechanisms of this response include host tissue injury, increased secretion of pro-inflammatory cytokines (TNF-α, IFN-γ, IL-1, IL-2, IL-12), and activation of dendritic cells (DCs), macrophages, NK cells, and cytotoxic T cells (109). Because of the low immunogenicity of human mesenchymal stem cells (HMSCs), some scholars have proposed (97) that BMSCs do not express the costimulatory molecules B7-1, B7-2, CD40, and CD40 ligands, and thus may not activate allogeneic reactive T cells.

However, in recent years, some scholars have proposed that although the immunogenicity of mesenchymal stem cells is low, thus fact alone does not explain why mesenchymal stem cells have “immune privileges” (10). Allogeneic MSCs transplanted into the body can still trigger immune rejection; however, at present, it is unclear whether this rejection has a major impact on the treatment effect. This article provides a detailed description of the above-mentioned factors that may affect host immune rejection.

Host Tissue Injury

In the treatment of osteoarthritis, Djouad et al. (110) initially proposed that although allogeneic mouse MSCs can be transplanted into mice with strong immunity to form bone, lymphocyte infiltration can be seen around newly formed tissues. Fischer et al. (111) also found more severe graft-versus-host disease (GVHD) in mice receiving allogeneic hematopoietic stem cell transplantation than in wild-type mice in clinical models. The main reason explaining this is that during allogeneic hematopoietic stem cell transplantation, damaged or dead epithelial cells release endogenous risk signals and are perceived by pattern recognition receptors on antigen-presenting cells, triggering the release of proinflammatory cytokines and T cells from major donor sources, which attack and destroy host cells and tissues, causing graft-versus-host disease (112).

In addition, studies have shown that the survival rate of allogeneic mesenchymal stem cells is limited when transplanted into the body. Liesz et al. proposed that even in uninjured adult brains, transplanted MSCs can be rejected within 14 days (113). This indicates that after allogeneic MSCs are transplanted into the body, the survival rate is still not guaranteed and some cannot coexist with the host. There are also reports that pigs (114), rats (115) and baboons (116) have dissolved allogeneic antibodies after inoculating allogeneic mesenchymal stem cells, which further confirmed the possibility of immune rejection between allogeneic and autologous MSCs.

Increased Secretion of Pro-Inflammatory Cytokines and Activation of Immunocytes

Barnhoorn et al. (117) showed that the titer of anti-donor immunoglobulin G increased significantly 7 days after the subcutaneous injection of IFN-γ-activated allogeneic mesenchymal stem cells in pigs. Furthermore, in the use of MSCs to treat traumatic brain injury, it has been proposed (54) that allogeneic mesenchymal stem cells can be actively rejected by the host immune response, mainly due to the cytotoxic CD8+ T cell-mediated response, which limits the therapeutic effect. Melissa et al. (51) released Fas ligand (FasL) through agarose gel to induce the apoptosis of cytotoxic CD8⁺ T cells, thereby reducing immune rejection induced by allogeneic mesenchymal stem cells during transplantation.

In addition, CD4⁺ Tm cells have been shown to induce allograft rejection by activating cytotoxic CD8⁺ T cells and helping B cells produce allogeneic antibodies (118, 119). Moreover, some scholars have found (120) that activated CD4 + T cells secrete IL-2 and IFN-γ, thereby damaging the structure of the extracellular matrix, precipitating extracellular collagen, promoting the proliferation of fibroblasts, and ultimately leading to immune rejection. It has also been suggested (121) that CD4⁺ helper T cells and monocytes can be recruited into the neointima and secrete IL-1, IL-6, and TNF-α, which enables smooth muscle cells to migrate and proliferate in the elastic layer of the endometrium, ultimately leading to graft-versus-host reaction (GVHR).

Current Treatment of Allogeneic MSCs Immune Rejection

At present, immune rejection of allogeneic mesenchymal stem cells still occurs. Some scholars have proposed that treatment can be refined by improving the persistence of mesenchymal stem cells and the immune tolerance of mesenchymal stem cells (10).

Improve the Persistence of MSCs

Recent advances have shown that solid organ transplantation can induce mixed hematopoietic chimerism in allogeneic MSC transplantation through donor hematopoietic stem cell transplantation (122). Moreover, the immunization isolation membrane device is used to temporarily prevent rejection by wrapping differentiated allogeneic cells in collagen or gelatin gels. Zanotti et al. have shown that subcutaneous injection of bone marrow MSCs wrapped in alginate can significantly improve their survival in GVHD mice (123).

In addition, in order to overcome the immune rejection caused by transplantation of allogeneic mesenchymal stem cells into the body and prolong the survival time of allogeneic mesenchymal stem cells, it is also necessary to ensure their persistence through host and MSC modification. For example, mesenchymal stem cells can be pre-treated or loaded with biological agents to increase the expression of surface receptors or the production of immunosuppressive cytokines (124).

Improving the Immune Tolerance of MSCs

In addition to improving immune tolerance, we can improve the efficacy of allogeneic MSCs by extending their survival time in vivo. On the one hand, the immune tolerance of allogeneic MSCs can be improved by treatment with exosomes or secreting nutritional and immunoregulatory cytokines to mediate hit-and-run mechanisms (125). However, it has also been proposed that the immune system can be reprogrammed through apoptotic bodies, thereby prolonging the duration of allogeneic MSCs after injection.

Induction Therapy

Induction therapy can be divided into T cell consumption and T cell non-consumption strategies. The former involves anti-thymocyte globulin (ATG), anti-CD3 antibody (OKT3), and alemtuzumab, which reduce the release of the proinflammatory cytokines TNF-α and IFN-γ by consuming T cells. While anti-IL-2 antibodies such as daclizumab, brazillicoxib, and anti-CD20 antibodies such as rituximab and anti-cytotoxin are considered non-depleting agents for T cells (126). IL-2, IL-6, and IL-1 are autophagy-related cytokines (63), and anti-IL-2 antibodies can reduce immune rejection by reducing autophagy induction.

New Direction of IUA Treatment: Autologous MSC

Autologous MSCs are safer to use because they use their own stem cells to avoid being attacked by B and T cells. In the treatment of IUA, in order not to affect subsequent fertility, the use of autologous MSCs is more in line with ethical requirements. Therefore, an increasing number of people are currently advocating the use of autologous MSCs for the treatment of female IUA. Such treatment reduces immune rejection, thereby reducing the recipient’s attack on the graft, while the female reproductive system avoids the controversy of potential genetic changes. In the treatment of intrauterine adhesions, this would also guarantee female fertility in later periods.

In 2011, a case study reported the implantation of autologous BMSCs into the uterine cavity in patients with severe IUA at 8 weeks of pregnancy (127). In 2014, a study found that the thickness of the endometrium slightly increased in patients with severe AS when they were injected with CD34+ or cultured autologous bone marrow stromal cells (128). In 2016, a case study reported the effect of injection of autologous peripheral blood CD133+ cells into the uterine spiral artery on endometrial reconstruction in 16 patients with refractory infertility (129). In the same year, 7 patients with severe IUA underwent autologous menstrual blood stromal cell transplantation, with two cases later successfully conceiving. In previous studies, transplantation of bone marrow/collagen complex into patients with severe IUA could help to achieve pregnancy and live birth after treatment (130). Our research group (131) recently proved that the combination of autologous adipose-derived mesenchymal stem cells (ADSCs) and gel can increase the endometrial thickness and reduce the fibrosis area through the BMP7-Smad5 pathway, resulting in successful conception.

Although transplantation with autologous MSCs is safer and more ethical than allogeneic MSCs, there are still some problems in the clinical applications. First, the number of extracted autologous MSCs is very limited as they can only be extracted from the host body (132). Second, after autologous MSCs are extracted, the in vitro culture cycle is long, which may not fully meet the needs of the body. Finally, there is a significant difference between the secretion and immune regulation of autologous MSCs (133).

Conclusion and Prospective

Immune rejection is very common in allogeneic transplantation and is one of the top five causes of death in patients undergoing allogeneic transplantation (134). To avoid adverse reactions, MSCs with low immunogenicity have become a research hotspot in recent years. However, some scholars have proposed that allogeneic mesenchymal stem cells can still trigger immune rejection. At present, the mechanism by which autologous MSCs avoid immune rejection is unclear. However, the experimental results showed that when autologous MSCs and allogeneic MSCs were injected into the body for treatment, autologous MSCs survived longer and there were clusters of immune cells around allogeneic MSCs (113).

In addition, IUA is an important factor affecting female infertility. The regenerative ability of MSCs can be harnessed repair and restore the function of the fibrotic endometrium. However, from an ethical point of view, it is still unclear whether allogeneic MSCs affect the development of offspring after implantation in the human body. Therefore, autologous MSCs are recommended for the treatment of IUA. At present, there is no effective method to solve the problem of extracting fewer stem cells from autologous MSCs, but the increase in exosomes may not only solve the problem of immune rejection of allogeneic MSCs, but also that of the low number of autologous MSCs.

Further studies to overcome the immune rejection caused by allogeneic MSCs during the treatment process are necessary. Owing to the many sources of allogeneic MSCs and the high efficiency of in vitro culture, the treatment of immune rejection caused by allogeneic MSCs is still receiving widespread attention (135). On the other hand, an obvious solution is to immediately use autologous MSCs as a ready-made product. In addition, new products such as acellular exosomes and MSCs derived from human pluripotent stem cells (hPSCs) are exciting developments that are attracting significant attention (136).

Funding

This work was supported by the Science and Technology Bureau of Quanzhou (grant number 2020CT003).

Publisher’s Note

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References

• 1

  HanYLiXZhangYHanYChangFDingJ. Mesenchymal Stem Cells for Regenerative Medicine. Cells (2019) 8:886. doi: 10.3390/cells8080886

  • CrossRef
  • Google Scholar

• 2

  HealyMWSchexnayderBConnellMTTerryNDeCherneyAHCsokmayJMet al. Intrauterine Adhesion Prevention After Hysteroscopy: A Systematic Review and Meta-Analysis. Am J Obstet Gynecol (2016) 215:267–75.e7. doi: 10.1016/j.ajog.2016.05.001

  • CrossRef
  • Google Scholar

• 3

  LeungRKLinYLiuY. Recent Advances in Understandings Towards Pathogenesis and Treatment for Intrauterine Adhesion and Disruptive Insights From Single-Cell Analysis. Reprod Sci (2021) 28:1812–26. doi: 10.1007/s43032-020-00343-y

  • CrossRef
  • Google Scholar

• 4

  Evans-HoekerEAYoungSL. Endometrial Receptivity and Intrauterine Adhesive Disease. Semin Reprod Med (2014) 32:392–401. doi: 10.1055/s-0034-1376358

  • CrossRef
  • Google Scholar

• 5

  AmerMIAbd-El-MaeboudKHAbdelfatahISalamaFAAbdallahAS. Human Amnion as a Temporary Biologic Barrier After Hysteroscopic Lysis of Severe Intrauterine Adhesions: Pilot Study. J Minim Invasive Gynecol (2010) 17:605–11. doi: 10.1016/j.jmig.2010.03.019

  • CrossRef
  • Google Scholar

• 6

  GuidaMAcunzoGDi Spiezio SardoABifulcoGPiccoliRPellicanoMet al. Effectiveness of Auto-Crosslinked Hyaluronic Acid Gel in the Prevention of Intrauterine Adhesions After Hysteroscopic Surgery: A Prospective, Randomized, Controlled Study. Hum Reprod (2004) 19:1461–4. doi: 10.1093/humrep/deh238

  • CrossRef
  • Google Scholar

• 7

  AziziRAghebati-MalekiLNouriMMarofiFNegargarSYousefiM. Stem Cell Therapy in Asherman Syndrome and Thin Endometrium: Stem Cell- Based Therapy. BioMed Pharmacother (2018) 102:333–43. doi: 10.1016/j.biopha.2018.03.091

  • CrossRef
  • Google Scholar

• 8

  CaoYSunHZhuHZhuXTangXYanGet al. Allogeneic Cell Therapy Using Umbilical Cord MSCs on Collagen Scaffolds for Patients With Recurrent Uterine Adhesion: A Phase I Clinical Trial. Stem Cell Res Ther (2018) 9:192. doi: 10.1186/s13287-018-0904-3

  • CrossRef
  • Google Scholar

• 9

  MambelliLIMattosRCWinterGHMadeiroDSMoraisBPMalschitzkyEet al. Changes in Expression Pattern of Selected Endometrial Proteins Following Mesenchymal Stem Cells Infusion in Mares With Endometrosis. PloS One (2014) 9:e97889. doi: 10.1371/journal.pone.0097889

  • CrossRef
  • Google Scholar

• 10

  AnkrumJAOngJFKarpJM. Mesenchymal Stem Cells: Immune Evasive, Not Immune Privileged. Nat Biotechnol (2014) 32:252–60. doi: 10.1038/nbt.2816

  • CrossRef
  • Google Scholar

• 11

  ShaoLZhangYPanXLiuBLiangCZhangYet al. Knockout of Beta-2 Microglobulin Enhances Cardiac Repair by Modulating Exosome Imprinting and Inhibiting Stem Cell-Induced Immune Rejection. Cell Mol Life Sci (2020) 77:937–52. doi: 10.1007/s00018-019-03220-3

  • CrossRef
  • Google Scholar

• 12

  ZangiLMargalitRReich-ZeligerSBachar-LustigEBeilhackANegrinRet al. Direct Imaging of Immune Rejection and Memory Induction by Allogeneic Mesenchymal Stromal Cells. Stem Cells (Dayton Ohio) (2009) 27:2865–74. doi: 10.1002/stem.217

  • CrossRef
  • Google Scholar

• 13

  MurphyNTreacyOLynchKMorcosMLohanPHowardLet al. TNF-Alpha/IL-1beta-Licensed Mesenchymal Stromal Cells Promote Corneal Allograft Survival via Myeloid Cell-Mediated Induction of Foxp3(+) Regulatory T Cells in the Lung. FASEB J (2019) 33:9404–21. doi: 10.1096/fj.201900047R

  • CrossRef
  • Google Scholar

• 14

  XuLHFangJPHongDLWuYF. Application of Mesenchymal Stromal Cells in Bone Marrow Transplantation for Sensitized Recipients. Acta Haematol (2012) 127:105–9. doi: 10.1159/000333554

  • CrossRef
  • Google Scholar

• 15

  KimSHanYSLeeJHLeeSH. Combination of MSC Spheroids Wrapped Within Autologous Composite Sheet Dually Protects Against Immune Rejection and Enhances Stem Cell Transplantation Efficacy. Tissue Cell (2018) 53:93–103. doi: 10.1016/j.tice.2018.06.005

  • CrossRef
  • Google Scholar

• 16

  DeansRAbbottJ. Review of Intrauterine Adhesions. J Minim Invasive Gynecol (2010) 17:555–69. doi: 10.1016/j.jmig.2010.04.016

  • CrossRef
  • Google Scholar

• 17

  SalazarCAIsaacsonKMorrisS. A Comprehensive Review of Asherman’s Syndrome: Causes, Symptoms and Treatment Options. Curr Opin Obstet Gynecol (2017) 29:249–56. doi: 10.1097/GCO.0000000000000378

  • CrossRef
  • Google Scholar

• 18

  Moquin-BeaudryGColasCLiYBazinRGuimondJVHaddadEet al. The Tumor-Immune Response Is Not Compromised by Mesenchymal Stromal Cells in Humanized Mice. J Immunol (Baltimore Md 1950) (2019) 203:2735–45. doi: 10.4049/jimmunol.1900807

  • CrossRef
  • Google Scholar

• 19

  SharmaJBSharmaESharmaSDharmendraS. Female Genital Tuberculosis: Revisited. Indian J Med Res (2018) 148:S71–83. doi: 10.4103/ijmr.IJMR_648_18

  • CrossRef
  • Google Scholar

• 20

  ChenYLiuLLuoYChenMHuanYFangR. Prevalence and Impact of Chronic Endometritis in Patients With Intrauterine Adhesions: A Prospective Cohort Study. J Minim Invasive Gynecol (2017) 24:74–9. doi: 10.1016/j.jmig.2016.09.022

  • CrossRef
  • Google Scholar

• 21

  DreislerEKjerJJ. Asherman’s Syndrome: Current Perspectives on Diagnosis and Management. Int J Womens Health (2019) 11:191–8. doi: 10.2147/IJWH.S165474

  • CrossRef
  • Google Scholar

• 22

  ZhaoXZhaoQZhuXHuangHWanXGuoRet al. Study on the Correlation Among Dysbacteriosis, Imbalance of Cytokine and the Formation of Intrauterine Adhesion. Ann Trans Med (2020) 8:52. doi: 10.21037/atm.2019.11.124

  • CrossRef
  • Google Scholar

• 23

  PlacekKSchultzeJLAschenbrennerAC. Epigenetic Reprogramming of Immune Cells in Injury, Repair, and Resolution. J Clin Invest (2019) 129:2994–3005. doi: 10.1172/JCI124619

  • CrossRef
  • Google Scholar

• 24

  YimamMLeeYCMooreBJiaoPHongMNamJBet al. Analgesic and Anti-Inflammatory Effects of UP1304, a Botanical Composite Containing Standardized Extracts of Curcuma Longa and Morus Alba. J Integr Med (2016) 14:60–8. doi: 10.1016/S2095-4964(16)60231-5

  • CrossRef
  • Google Scholar

• 25

  WangXMaNSunQHuangCLiuYLuoX. Elevated NF-kappaB Signaling in Asherman Syndrome Patients and Animal Models. Oncotarget (2017) 8:15399–406. doi: 10.18632/oncotarget.14853

  • CrossRef
  • Google Scholar

• 26

  LinXNZhouFWeiMLYangYLiYLiTCet al. Randomized, Controlled Trial Comparing the Efficacy of Intrauterine Balloon and Intrauterine Contraceptive Device in the Prevention of Adhesion Reformation After Hysteroscopic Adhesiolysis. Fertil Steril (2015) 104:235–40. doi: 10.1016/j.fertnstert.2015.04.008

  • CrossRef
  • Google Scholar

• 27

  MoghaddamASAfshariJTEsmaeiliSASaburiEJoneidiZMomtazi-BorojeniAA. Cardioprotective microRNAs: Lessons From Stem Cell-Derived Exosomal microRNAs to Treat Cardiovascular Disease. Atherosclerosis (2019) 285:1–9. doi: 10.1016/j.atherosclerosis.2019.03.016

  • CrossRef
  • Google Scholar

• 28

  MaisVCirronisMGPeirettiMFerrucciGCossuEMelisGB. Efficacy of Auto-Crosslinked Hyaluronan Gel for Adhesion Prevention in Laparoscopy and Hysteroscopy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Eur J Obstet Gynecol Reprod Biol (2012) 160:1–5. doi: 10.1016/j.ejogrb.2011.08.002

  • CrossRef
  • Google Scholar

• 29

  ChiYHePLeiLLanYHuJMengYet al. Transdermal Estrogen Gel and Oral Aspirin Combination Therapy Improves Fertility Prognosis via the Promotion of Endometrial Receptivity in Moderate to Severe Intrauterine Adhesion. Mol Med Rep (2018) 17:6337–44. doi: 10.3892/mmr.2018.8685

  • CrossRef
  • Google Scholar

• 30

  HanstedeMMvan der MeijEGoedemansLEmanuelMH. Results of Centralized Asherman Surgery, 2003-2013. Fertil Steril (2015) 104:1561–8 e1. doi: 10.1016/j.fertnstert.2015.08.039

  • CrossRef
  • Google Scholar

• 31

  XinLLinXPanYZhengXShiLZhangYet al. A Collagen Scaffold Loaded With Human Umbilical Cord-Derived Mesenchymal Stem Cells Facilitates Endometrial Regeneration and Restores Fertility. Acta Biomater (2019) 92:160–71. doi: 10.1016/j.actbio.2019.05.012

  • CrossRef
  • Google Scholar

• 32

  WangLYuCChangTZhangMSongSXiongCet al. In Situ Repair Abilities of Human Umbilical Cord-Derived Mesenchymal Stem Cells and Autocrosslinked Hyaluronic Acid Gel Complex in Rhesus Monkeys With Intrauterine Adhesion. Sci Adv (2020) 6:eaba6357. doi: 10.1126/sciadv.aba6357

  • CrossRef
  • Google Scholar

• 33

  FeiZXinXFeiHCuiYC. Meta-Analysis of the Use of Hyaluronic Acid Gel to Prevent Intrauterine Adhesions After Miscarriage. Eur J Obstet Gyn R B (2020) 244:1–4. doi: 10.1016/j.ejogrb.2019.10.018

  • CrossRef
  • Google Scholar

• 34

  XinLBLinXNZhouFLiCWangXFYuHYet al. A Scaffold Laden With Mesenchymal Stem Cell-Derived Exosomes for Promoting Endometrium Regeneration and Fertility Restoration Through Macrophage Immunomodulation. Acta Biomaterialia (2020) 113:252–66. doi: 10.1016/j.actbio.2020.06.029

  • CrossRef
  • Google Scholar

• 35

  UccelliAMorettaLPistoiaV. Mesenchymal Stem Cells in Health and Disease. Nat Rev Immunol (2008) 8:726–36. doi: 10.1038/nri2395

  • CrossRef
  • Google Scholar

• 36

  ElahiKCKleinGAvci-AdaliMSievertKDMacNeilSAicherWK. Human Mesenchymal Stromal Cells From Different Sources Diverge in Their Expression of Cell Surface Proteins and Display Distinct Differentiation Patterns. Stem Cells Int (2016) 2016:5646384. doi: 10.1155/2016/5646384

  • CrossRef
  • Google Scholar

• 37

  CostaLAEiroNFraileMGonzalezLOSaaJGarcia-PortabellaPet al. Functional Heterogeneity of Mesenchymal Stem Cells From Natural Niches to Culture Conditions: Implications for Further Clinical Uses. Cell Mol Life Sci (2021) 78:447–67. doi: 10.1007/s00018-020-03600-0

  • CrossRef
  • Google Scholar

• 38

  MontiMPerottiCDel FanteCCervioMRediCAFondazione Irccs Policlinico San MatteoP. Stem Cells: Sources and Therapies. Biol Res (2012) 45:207–14. doi: 10.4067/S0716-97602012000300002

  • CrossRef
  • Google Scholar

• 39

  Khan-FarooqiHChodoshJ. Autologous Limbal Stem Cell Transplantation: The Progression of Diagnosis and Treatment. Semin Ophthalmol (2016) 31:91–8. doi: 10.3109/08820538.2015.1114862

  • CrossRef
  • Google Scholar

• 40

  PetrouPKassisILevinNPaulFBacknerYBenolielTet al. Beneficial Effects of Autologous Mesenchymal Stem Cell Transplantation in Active Progressive Multiple Sclerosis. Brain (2020) 143:3574–88. doi: 10.1093/brain/awaa333

  • CrossRef
  • Google Scholar

• 41

  ZahorecPSarkozyovaNFerancikovaNBukovcanPDanisovicLBohacMet al. Autologous Mesenchymal Stem Cells Application in Post-Burn Scars Treatment: A Preliminary Study. Cell Tissue Bank (2021) 22:39–46. doi: 10.1007/s10561-020-09862-z

  • CrossRef
  • Google Scholar

• 42

  LightnerALDozoisEJDietzABFletcherJGFritonJButlerGet al. Matrix-Delivered Autologous Mesenchymal Stem Cell Therapy for Refractory Rectovaginal Crohn’s Fistulas. Inflamm Bowel Dis (2020) 26:670–7. doi: 10.1093/ibd/izz215

  • CrossRef
  • Google Scholar

• 43

  RuanoDLopez-MartinJAMorenoLLassalettaABautistaFAndionMet al. First-In-Human, First-In-Child Trial of Autologous MSCs Carrying the Oncolytic Virus Icovir-5 in Patients With Advanced Tumors. Mol Ther (2020) 28:1033–42. doi: 10.1016/j.ymthe.2020.01.019

  • CrossRef
  • Google Scholar

• 44

  SharpePT. Dental Mesenchymal Stem Cells. Development (2016) 143:2273–80. doi: 10.1242/dev.134189

  • CrossRef
  • Google Scholar

• 45

  DingDCChangYHShyuWCLinSZ. Human Umbilical Cord Mesenchymal Stem Cells: A New Era for Stem Cell Therapy. Cell Transplant (2015) 24:339–47. doi: 10.3727/096368915X686841

  • CrossRef
  • Google Scholar

• 46

  BakerNBoyetteLBTuanRS. Characterization of Bone Marrow-Derived Mesenchymal Stem Cells in Aging. Bone (2015) 70:37–47. doi: 10.1016/j.bone.2014.10.014

  • CrossRef
  • Google Scholar

• 47

  BourinPBunnellBACasteillaLDominiciMKatzAJMarchKLet al. Stromal Cells From the Adipose Tissue-Derived Stromal Vascular Fraction and Culture Expanded Adipose Tissue-Derived Stromal/Stem Cells: A Joint Statement of the International Federation for Adipose Therapeutics and Science (IFATS) and the International Society for Cellular Therapy (ISCT). Cytotherapy (2013) 15:641–8. doi: 10.1016/j.jcyt.2013.02.006

  • CrossRef
  • Google Scholar

• 48

  MakiCBBeckAWallisCCCChooJRamosTTongRet al. Intra-Articular Administration of Allogeneic Adipose Derived MSCs Reduces Pain and Lameness in Dogs With Hip Osteoarthritis: A Double Blinded, Randomized, Placebo Controlled Pilot Study. Front Vet Sci (2020) 7:570. doi: 10.3389/fvets.2020.00570

  • CrossRef
  • Google Scholar

• 49

  ZhengGHuangLTongHShuQHuYGeMet al. Treatment of Acute Respiratory Distress Syndrome With Allogeneic Adipose-Derived Mesenchymal Stem Cells: A Randomized, Placebo-Controlled Pilot Study. Respir Res (2014) 15:39. doi: 10.1186/1465-9921-15-39

  • CrossRef
  • Google Scholar

• 50

  AkitaNNaritaYYamawaki-OgataAUsuiAKomoriK. Therapeutic Effect of Allogeneic Bone Marrow-Derived Mesenchymal Stromal Cells on Aortic Aneurysms. Cell Tissue Res (2021) 383:781–93. doi: 10.1007/s00441-020-03295-6

  • CrossRef
  • Google Scholar

• 51

  Alvarado-VelezMEnamSFMehtaNLyonJGLaPlacaMCBellamkondaRV. Immuno-Suppressive Hydrogels Enhance Allogeneic MSC Survival After Transplantation in the Injured Brain. Biomaterials (2021) 266:120419. doi: 10.1016/j.biomaterials.2020.120419

  • CrossRef
  • Google Scholar

• 52

  ChengYHDongJCBianQ. Small Molecules for Mesenchymal Stem Cell Fate Determination. World J Stem Cells (2019) 11:1084–103. doi: 10.4252/wjsc.v11.i12.1084

  • CrossRef
  • Google Scholar

• 53

  HsiaoCYChenTHHuangBSChenPHSuCHShyuJFet al. Comparison Between the Therapeutic Effects of Differentiated and Undifferentiated Wharton’s Jelly Mesenchymal Stem Cells in Rats With Streptozotocin-Induced Diabetes. World J Stem Cells (2020) 12:139–51. doi: 10.4252/wjsc.v12.i2.139

  • CrossRef
  • Google Scholar

• 54

  WangYChenXCaoWShiY. Plasticity of Mesenchymal Stem Cells in Immunomodulation: Pathological and Therapeutic Implications. Nat Immunol (2014) 15:1009–16. doi: 10.1038/ni.3002

  • CrossRef
  • Google Scholar

• 55

  MutluLHufnagelDTaylorHS. The Endometrium as a Source of Mesenchymal Stem Cells for Regenerative Medicine. Biol Reprod (2015) 92:138. doi: 10.1095/biolreprod.114.126771

  • CrossRef
  • Google Scholar

• 56

  BenorAGaySDeCherneyA. An Update on Stem Cell Therapy for Asherman Syndrome. J Assisted Reprod Genet (2020) 37:1511–29. doi: 10.1007/s10815-020-01801-x

  • CrossRef
  • Google Scholar

• 57

  Luz-CrawfordPKurteMBravo-AlegriaJContrerasRNova-LampertiETejedorGet al. Mesenchymal Stem Cells Generate a CD4+CD25+Foxp3+ Regulatory T Cell Population During the Differentiation Process of Th1 and Th17 Cells. Stem Cell Res Ther (2013) 4:65. doi: 10.1186/scrt216

  • CrossRef
  • Google Scholar

• 58

  JiangYZhangPZhangXLvLZhouY. Advances in Mesenchymal Stem Cell Transplantation for the Treatment of Osteoporosis. Cell Prolif (2021) 54:e12956. doi: 10.1111/cpr.12956

  • CrossRef
  • Google Scholar

• 59

  NemethKMayerBMezeyE. Modulation of Bone Marrow Stromal Cell Functions in Infectious Diseases by Toll-Like Receptor Ligands. J Mol Med (Berl) (2010) 88:5–10. doi: 10.1007/s00109-009-0523-7

  • CrossRef
  • Google Scholar

• 60

  WatermanRSTomchuckSLHenkleSLBetancourtAM. A New Mesenchymal Stem Cell (MSC) Paradigm: Polarization Into a Pro-Inflammatory MSC1 or an Immunosuppressive MSC2 Phenotype. PloS One (2010) 5:e10088. doi: 10.1371/journal.pone.0010088

  • CrossRef
  • Google Scholar

• 61

  LiottaFAngeliRCosmiLFiliLManuelliCFrosaliFet al. Toll-Like Receptors 3 and 4 are Expressed by Human Bone Marrow-Derived Mesenchymal Stem Cells and can Inhibit Their T-Cell Modulatory Activity by Impairing Notch Signaling. Stem Cells (Dayton Ohio) (2008) 26:279–89. doi: 10.1634/stemcells.2007-0454

  • CrossRef
  • Google Scholar

• 62

  LiuDWangJZhaoGJiangPSongMDingHet al. CSF1-Associated Decrease in Endometrial Macrophages may Contribute to Asherman’s Syndrome. Am J Reprod Immunol (2020) 83:e13191. doi: 10.1111/aji.13191

  • CrossRef
  • Google Scholar

• 63

  LiBZhangQSunJLaiD. Human Amniotic Epithelial Cells Improve Fertility in an Intrauterine Adhesion Mouse Model. Stem Cell Res Ther (2019) 10:257. doi: 10.1186/s13287-019-1368-9

  • CrossRef
  • Google Scholar

• 64

  TakanoHOhtsukaMAkazawaHTokoHHaradaMHasegawaHet al. Pleiotropic Effects of Cytokines on Acute Myocardial Infarction: G-CSF as a Novel Therapy for Acute Myocardial Infarction. Curr Pharm Des (2003) 9:1121–7. doi: 10.2174/1381612033455008

  • CrossRef
  • Google Scholar

• 65

  NagoriCBPanchalSYPatelH. Endometrial Regeneration Using Autologous Adult Stem Cells Followed by Conception by In Vitro Fertilization in a Patient of Severe Asherman’s Syndrome. J Hum Reprod Sci (2011) 4:43–8. doi: 10.4103/0974-1208.82360

  • CrossRef
  • Google Scholar

• 66

  WolffEFMutluLMassasaEEElsworthJDEugene RedmondDJr.TaylorHS. Endometrial Stem Cell Transplantation in MPTP- Exposed Primates: An Alternative Cell Source for Treatment of Parkinson’s Disease. J Cell Mol Med (2015) 19:249–56. doi: 10.1111/jcmm.12433

  • CrossRef
  • Google Scholar

• 67

  WolffEFGaoXBYaoKVAndrewsZBDuHElsworthJDet al. Endometrial Stem Cell Transplantation Restores Dopamine Production in a Parkinson’s Disease Model. J Cell Mol Med (2011) 15:747–55. doi: 10.1111/j.1582-4934.2010.01068.x

  • CrossRef
  • Google Scholar

• 68

  NoureddiniMVerdiJMortazavi-TabatabaeiSASharifSAzimiAKeyhanvarPet al. Human Endometrial Stem Cell Neurogenesis in Response to NGF and bFGF. Cell Biol Int (2012) 36:961–6. doi: 10.1042/CBI20110610

  • CrossRef
  • Google Scholar

• 69

  Ebrahimi-BaroughSKouchesfahaniHMAiJMassumiM. Differentiation of Human Endometrial Stromal Cells Into Oligodendrocyte Progenitor Cells (OPCs). J Mol Neurosci (2013) 51:265–73. doi: 10.1007/s12031-013-9957-z

  • CrossRef
  • Google Scholar

• 70

  SantamariaXMassasaEEFengYWolffETaylorHS. Derivation of Insulin Producing Cells From Human Endometrial Stromal Stem Cells and Use in the Treatment of Murine Diabetes. Mol Ther (2011) 19:2065–71. doi: 10.1038/mt.2011.173

  • CrossRef
  • Google Scholar

• 71

  HidaNNishiyamaNMiyoshiSKiraSSegawaKUyamaTet al. Novel Cardiac Precursor-Like Cells From Human Menstrual Blood-Derived Mesenchymal Cells. Stem Cells (2008) 26:1695–704. doi: 10.1634/stemcells.2007-0826

  • CrossRef
  • Google Scholar

• 72

  WangJChenSZhangCStegemanSPfaff-AmesseTZhangYet al. Human Endometrial Stromal Stem Cells Differentiate Into Megakaryocytes With the Ability to Produce Functional Platelets. PloS One (2012) 7:e44300. doi: 10.1371/journal.pone.0044300

  • CrossRef
  • Google Scholar

• 73

  Shoae-HassaniAMortazavi-TabatabaeiSASharifSSeifalianAMAzimiASamadikuchaksaraeiAet al. Differentiation of Human Endometrial Stem Cells Into Urothelial Cells on a Three-Dimensional Nanofibrous Silk-Collagen Scaffold: An Autologous Cell Resource for Reconstruction of the Urinary Bladder Wall. J Tissue Eng Regener Med (2015) 9:1268–76. doi: 10.1002/term.1632

  • CrossRef
  • Google Scholar

• 74

  WalterJWareLBMatthayMA. Mesenchymal Stem Cells: Mechanisms of Potential Therapeutic Benefit in ARDS and Sepsis. Lancet Respir Med (2014) 2:1016–26. doi: 10.1016/S2213-2600(14)70217-6

  • CrossRef
  • Google Scholar

• 75

  PegtelDMGouldSJ. Exosomes. Annu Rev Biochem (2019) 88:487–514. doi: 10.1146/annurev-biochem-013118-111902

  • CrossRef
  • Google Scholar

• 76

  KalluriRLeBleuVS. The Biology, Function, and Biomedical Applications of Exosomes. Science (2020) 367:eaau6977. doi: 10.1126/science.aau6977

  • CrossRef
  • Google Scholar

• 77

  YaoYChenRWangGZhangYLiuF. Exosomes Derived From Mesenchymal Stem Cells Reverse EMT via TGF-Beta1/Smad Pathway and Promote Repair of Damaged Endometrium. Stem Cell Res Ther (2019) 10:225. doi: 10.1186/s13287-019-1332-8

  • CrossRef
  • Google Scholar

• 78

  LiaoZLiuCWangLSuiCZhangH. Therapeutic Role of Mesenchymal Stem Cell-Derived Extracellular Vesicles in Female Reproductive Diseases. Front Endocrinol (2021) 12:665645. doi: 10.3389/fendo.2021.665645

  • CrossRef
  • Google Scholar

• 79

  LiangXZhangLWangSHanQZhaoRC. Exosomes Secreted by Mesenchymal Stem Cells Promote Endothelial Cell Angiogenesis by Transferring miR-125a. J Cell Sci (2016) 129:2182–9. doi: 10.1242/jcs.170373

  • CrossRef
  • Google Scholar

• 80

  ZhaoSQiWZhengJTianYQiXKongDet al. Exosomes Derived From Adipose Mesenchymal Stem Cells Restore Functional Endometrium in a Rat Model of Intrauterine Adhesions. Reprod Sci (Thousand Oaks Calif) (2020) 27:1266–75. doi: 10.1007/s43032-019-00112-6

  • CrossRef
  • Google Scholar

• 81

  TanQXiaDYingX. miR-29a in Exosomes From Bone Marrow Mesenchymal Stem Cells Inhibit Fibrosis During Endometrial Repair of Intrauterine Adhesion. Int J Stem Cells (2020) 13:414–23. doi: 10.15283/ijsc20049

  • CrossRef
  • Google Scholar

• 82

  XiaoLSongYHuangWYangSFuJFengXet al. Expression of SOX2, NANOG and OCT4 in a Mouse Model of Lipopolysaccharide-Induced Acute Uterine Injury and Intrauterine Adhesions. Reprod Biol Endocrinol (2017) 15:14. doi: 10.1186/s12958-017-0234-9

  • CrossRef
  • Google Scholar

• 83

  WangXGaoYShiHLiuNZhangWLiH. Influence of the Intensity and Loading Time of Direct Current Electric Field on the Directional Migration of Rat Bone Marrow Mesenchymal Stem Cells. Front Med (2016) 10:286–96. doi: 10.1007/s11684-016-0456-9

  • CrossRef
  • Google Scholar

• 84

  ZhouQWuXHuJYuanR. Abnormal Expression of Fibrosis Markers, Estrogen Receptor Alpha and Stromal Derived Factor1/Chemokine (CXC Motif) Receptor4 Axis in Intrauterine Adhesions. Int J Mol Med (2018) 42:81–90. doi: 10.3892/ijmm.2018.3586

  • CrossRef
  • Google Scholar

• 85

  Sahin ErsoyGZolbinMMCosarEMoridiIMamillapalliRTaylorHS. CXCL12 Promotes Stem Cell Recruitment and Uterine Repair After Injury in Asherman’s Syndrome. Mol Ther Methods Clin Dev (2017) 4:169–77. doi: 10.1016/j.omtm.2017.01.001

  • CrossRef
  • Google Scholar

• 86

  DuHNaqviHTaylorHS. Ischemia/reperfusion Injury Promotes and Granulocyte-Colony Stimulating Factor Inhibits Migration of Bone Marrow-Derived Stem Cells to Endometrium. Stem Cells Dev (2012) 21:3324–31. doi: 10.1089/scd.2011.0193

  • CrossRef
  • Google Scholar

• 87

  Sanabria-de la TorreRQuiñones-VicoMIFernández-GonzálezASánchez-DíazMMontero-VílchezTSierra-SánchezÁet al. Alloreactive Immune Response Associated to Human Mesenchymal Stromal Cells Treatment: A Systematic Review. J Clin Med (2021) 10:2991. doi: 10.3390/jcm10132991

  • CrossRef
  • Google Scholar

• 88

  Le BlancKTammikCRosendahlKZetterbergERingdenO. HLA Expression and Immunologic Properties of Differentiated and Undifferentiated Mesenchymal Stem Cells. Exp Hematol (2003) 31:890–6. doi: 10.1016/S0301-472X(03)00110-3

  • CrossRef
  • Google Scholar

• 89

  KramperaM. Mesenchymal Stromal Cell ’Licensing’: A Multistep Process. Leukemia (2011) 25:1408–14. doi: 10.1038/leu.2011.108

  • CrossRef
  • Google Scholar

• 90

  MullerLTungerAWobusMvon BoninMTowersRBornhauserMet al. Immunomodulatory Properties of Mesenchymal Stromal Cells: An Update. Front Cell Dev Biol (2021) 9:637725. doi: 10.3389/fcell.2021.637725

  • CrossRef
  • Google Scholar

• 91

  Shapouri-MoghaddamAMohammadianSVaziniHTaghadosiMEsmaeiliSAMardaniFet al. Macrophage Plasticity, Polarization, and Function in Health and Disease. J Cell Physiol (2018) 233:6425–40. doi: 10.1002/jcp.26429

  • CrossRef
  • Google Scholar

• 92

  YangRGaoHChenLFangNChenHSongGet al. Effect of Peripheral Blood-Derived Mesenchymal Stem Cells on Macrophage Polarization and Th17/Treg Balance In Vitro. Regener Ther (2020) 14:275–83. doi: 10.1016/j.reth.2020.03.008

  • CrossRef
  • Google Scholar

• 93

  MaqboolMAlgraitteeSJRBoroojerdiMHSarmadiVHJohnCMVidyadaranSet al. Human Mesenchymal Stem Cells Inhibit the Differentiation and Effector Functions of Monocytes. Innate Immun (2020) 26:424–34. doi: 10.1177/1753425919899132

  • CrossRef
  • Google Scholar

• 94

  de WitteSFHLukFSierra ParragaJMGargeshaMMerinoAKorevaarSSet al. Immunomodulation By Therapeutic Mesenchymal Stromal Cells (MSC) Is Triggered Through Phagocytosis of MSC By Monocytic Cells. Stem Cells (Dayton Ohio) (2018) 36:602–15. doi: 10.1002/stem.2779

  • CrossRef
  • Google Scholar

• 95

  DongLChenXShaoHBaiLLiXZhangX. Mesenchymal Stem Cells Inhibited Dendritic Cells Via the Regulation of STAT1 and STAT6 Phosphorylation in Experimental Autoimmune Uveitis. Curr Mol Med (2018) 17:478–87. doi: 10.2174/1566524018666180207155614

  • CrossRef
  • Google Scholar

• 96

  LuZMengSChangWFanSXieJGuoFet al. Mesenchymal Stem Cells Activate Notch Signaling to Induce Regulatory Dendritic Cells in LPS-Induced Acute Lung Injury. J Trans Med (2020) 18:241. doi: 10.1186/s12967-020-02410-z

  • CrossRef
  • Google Scholar

• 97

  AggarwalSPittengerMF. Human Mesenchymal Stem Cells Modulate Allogeneic Immune Cell Responses. Blood (2005) 105:1815–22. doi: 10.1182/blood-2004-04-1559

  • CrossRef
  • Google Scholar

• 98

  ShahirMMahmoud HashemiSAsadiradAVarahramMKazempour-DizajiMFolkertsGet al. Effect of Mesenchymal Stem Cell-Derived Exosomes on the Induction of Mouse Tolerogenic Dendritic Cells. J Cell Physiol (2020) 235:7043–55. doi: 10.1002/jcp.29601

  • CrossRef
  • Google Scholar

• 99

  KramperaMGlennieSDysonJScottDLaylorRSimpsonEet al. Bone Marrow Mesenchymal Stem Cells Inhibit the Response of Naive and Memory Antigen-Specific T Cells to Their Cognate Peptide. Blood (2003) 101:3722–9. doi: 10.1182/blood-2002-07-2104

  • CrossRef
  • Google Scholar

• 100

  KramperaMCosmiLAngeliRPasiniALiottaFAndreiniAet al. Role for Interferon-Gamma in the Immunomodulatory Activity of Human Bone Marrow Mesenchymal Stem Cells. Stem Cells (Dayton Ohio) (2006) 24:386–98. doi: 10.1634/stemcells.2005-0008

  • CrossRef
  • Google Scholar

• 101

  LeeSKimSChungHMoonJHKangSJParkCG. Mesenchymal Stem Cell-Derived Exosomes Suppress Proliferation of T Cells by Inducing Cell Cycle Arrest Through P27kip1/Cdk2 Signaling. Immunol Lett (2020) 225:16–22. doi: 10.1016/j.imlet.2020.06.006

  • CrossRef
  • Google Scholar

• 102

  GeWJiangJArpJLiuWGarciaBWangH. Regulatory T-Cell Generation and Kidney Allograft Tolerance Induced by Mesenchymal Stem Cells Associated With Indoleamine 2,3-Dioxygenase Expression. Transplantation (2010) 90:1312–20. doi: 10.1097/TP.0b013e3181fed001

  • CrossRef
  • Google Scholar

• 103

  GuoLLaiPWangYHuangTChenXLuoCet al. Extracellular Vesicles From Mesenchymal Stem Cells Prevent Contact Hypersensitivity Through the Suppression of Tc1 and Th1 Cells and Expansion of Regulatory T Cells. Int Immunopharmacol (2019) 74:105663. doi: 10.1016/j.intimp.2019.05.048

  • CrossRef
  • Google Scholar

• 104

  Justiz VaillantAAMohseniM. Chronic Transplantation Rejection. Treasure Island (FL: StatPearls (2021).

  • Google Scholar

• 105

  ElfenbeinGJSacksteinR. Primed Marrow for Autologous and Allogeneic Transplantation: A Review Comparing Primed Marrow to Mobilized Blood and Steady-State Marrow. Exp Hematol (2004) 32:327–39. doi: 10.1016/j.exphem.2004.01.010

  • CrossRef
  • Google Scholar

• 106

  TabbaraIAKairouzSNahlehZMihalceaAM. Current Concepts in Allogeneic Hematopoietic Stem Cell Transplantation. Anticancer Res (2003) 23:5055–67.

  • Google Scholar

• 107

  ZengDLanFHoffmannPStroberS. Suppression of Graft-Versus-Host Disease by Naturally Occurring Regulatory T Cells. Transplantation (2004) 77:S9–S11. doi: 10.1097/01.TP.0000106475.38978.11

  • CrossRef
  • Google Scholar

• 108

  SlavinS. Graft-Versus-Host Disease, the Graft-Versus-Leukemia Effect, and Mixed Chimerism Following Nonmyeloablative Stem Cell Transplantation. Int J Hematol (2003) 78:195–207. doi: 10.1007/BF02983795

  • CrossRef
  • Google Scholar

• 109

  van den BrinkMRBurakoffSJ. Cytolytic Pathways in Haematopoietic Stem-Cell Transplantation. Nat Rev Immunol (2002) 2:273–81. doi: 10.1038/nri775

  • CrossRef
  • Google Scholar

• 110

  DjouadFPlencePBonyCTropelPApparaillyFSanyJet al. Immunosuppressive Effect of Mesenchymal Stem Cells Favors Tumor Growth in Allogeneic Animals. Blood (2003) 102:3837–44. doi: 10.1182/blood-2003-04-1193

  • CrossRef
  • Google Scholar

• 111

  FischerJCBscheiderMEisenkolbGLinCCWintgesAOttenVet al. RIG-I/MAVS and STING Signaling Promote Gut Integrity During Irradiation- and Immune-Mediated Tissue Injury. Sci Transl Med (2017) 9:eaag2513. doi: 10.1126/scitranslmed.aag2513

  • CrossRef
  • Google Scholar

• 112

  HeideggerSvan den BrinkMRHaasTPoeckH. The Role of Pattern-Recognition Receptors in Graft-Versus-Host Disease and Graft-Versus-Leukemia After Allogeneic Stem Cell Transplantation. Front Immunol (2014) 5:337. doi: 10.3389/fimmu.2014.00337

  • CrossRef
  • Google Scholar

• 113

  LieszADalpkeAMracskoEAntoineDJRothSZhouWet al. DAMP Signaling Is a Key Pathway Inducing Immune Modulation After Brain Injury. J Neurosci (2015) 35:583–98. doi: 10.1523/JNEUROSCI.2439-14.2015

  • CrossRef
  • Google Scholar

• 114

  ChoPSMessinaDJHirshELChiNGoldmanSNLoDPet al. Immunogenicity of Umbilical Cord Tissue Derived Cells. Blood (2008) 111:430–8. doi: 10.1182/blood-2007-03-078774

  • CrossRef
  • Google Scholar

• 115

  SchuSNosovMO’FlynnLShawGTreacyOBarryFet al. Immunogenicity of Allogeneic Mesenchymal Stem Cells. J Cell Mol Med (2012) 16:2094–103. doi: 10.1111/j.1582-4934.2011.01509.x

  • CrossRef
  • Google Scholar

• 116

  BeggsKJLyubimovABornemanJNBartholomewAMoseleyADoddsRet al. Immunologic Consequences of Multiple, High-Dose Administration of Allogeneic Mesenchymal Stem Cells to Baboons. Cell Transplant (2006) 15:711–21. doi: 10.3727/000000006783981503

  • CrossRef
  • Google Scholar

• 117

  BarnhoornMCVan HalterenAGSVan PelMMolendijkIStruijkACJansenPMet al. Lymphoproliferative Disease in the Rectum 4 Years After Local Mesenchymal Stromal Cell Therapy for Refractory Perianal Crohn’s Fistulas: A Case Report. J Crohns Colitis (2019) 13:807–11. doi: 10.1093/ecco-jcc/jjy220

  • CrossRef
  • Google Scholar

• 118

  ZhangQWRabantMSchenkAValujskikhA. ICOS-Dependent and -Independent Functions of Memory CD4 T Cells in Allograft Rejection. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surgeons (2008) 8:497–506. doi: 10.1111/j.1600-6143.2007.02096.x

  • CrossRef
  • Google Scholar

• 119

  ChenYHeegerPSValujskikhA. In Vivo Helper Functions of Alloreactive Memory CD4+ T Cells Remain Intact Despite Donor-Specific Transfusion and Anti-CD40 Ligand Therapy. J Immunol (Baltimore Md 1950) (2004) 172:5456–66. doi: 10.4049/jimmunol.172.9.5456

  • CrossRef
  • Google Scholar

• 120

  PichlerMRainerPPSchauerSHoeflerG. Cardiac Fibrosis in Human Transplanted Hearts is Mainly Driven by Cells of Intracardiac Origin. J Am Coll Cardiol (2012) 59:1008–16. doi: 10.1016/j.jacc.2011.11.036

  • CrossRef
  • Google Scholar

• 121

  ChihSChongAYMielniczukLMBhattDLBeanlandsRS. Allograft Vasculopathy: The Achilles’ Heel of Heart Transplantation. J Am Coll Cardiol (2016) 68:80–91. doi: 10.1016/j.jacc.2016.04.033

  • CrossRef
  • Google Scholar

• 122

  LeonardDACetruloCLJr.McGroutherDASachsDH. Induction of Tolerance of Vascularized Composite Allografts. Transplantation (2013) 95:403–9. doi: 10.1097/TP.0b013e31826d886d

  • CrossRef
  • Google Scholar

• 123

  ZanottiLSarukhanADanderECastorMCibellaJSoldaniCet al. Encapsulated Mesenchymal Stem Cells for In Vivo Immunomodulation. Leukemia (2013) 27:500–3. doi: 10.1038/leu.2012.202

  • CrossRef
  • Google Scholar

• 124

  AnkrumJAMirandaORNgKSSarkarDXuCKarpJM. Engineering Cells With Intracellular Agent-Loaded Microparticles to Control Cell Phenotype. Nat Protoc (2014) 9:233–45. doi: 10.1038/nprot.2014.002

  • CrossRef
  • Google Scholar

• 125

  ProckopDJ. Concise Review: Two Negative Feedback Loops Place Mesenchymal Stem/Stromal Cells at the Center of Early Regulators of Inflammation. Stem Cells (Dayton Ohio) (2013) 31:2042–6. doi: 10.1002/stem.1400

  • CrossRef
  • Google Scholar

• 126

  ZhaoLHuCHanFChenDChengJWuJet al. Induction Therapy With Mesenchymal Stromal Cells in Kidney Transplantation: A Meta-Analysis. Stem Cell Res Ther (2021) 12:158. doi: 10.1186/s13287-021-02219-7

  • CrossRef
  • Google Scholar

• 127

  WangHJinPSabatinoMRenJCiviniSBoginVet al. Comparison of Endometrial Regenerative Cells and Bone Marrow Stromal Cells. J Trans Med (2012) 10:207. doi: 10.1186/1479-5876-10-207

  • CrossRef
  • Google Scholar

• 128

  SinghNMohantySSethTShankarMBhaskaranSDharmendraS. Autologous Stem Cell Transplantation in Refractory Asherman’s Syndrome: A Novel Cell Based Therapy. J Hum Reprod Sci (2014) 7:93–8. doi: 10.4103/0974-1208.138864

  • CrossRef
  • Google Scholar

• 129

  SantamariaXCabanillasSCervellóIArbonaCRagaFFerroJet al. Autologous Cell Therapy With CD133+ Bone Marrow-Derived Stem Cells for Refractory Asherman’s Syndrome and Endometrial Atrophy: A Pilot Cohort Study. Hum Reprod (Oxford England) (2016) 31:1087–96. doi: 10.1093/humrep/dew042

  • CrossRef
  • Google Scholar

• 130

  ZhaoGCaoYZhuXTangXDingLSunHet al. Transplantation of Collagen Scaffold With Autologous Bone Marrow Mononuclear Cells Promotes Functional Endometrium Reconstruction via Downregulating DeltaNp63 Expression in Asherman’s Syndrome. Sci China Life Sci (2017) 60:404–16. doi: 10.1007/s11427-016-0328-y

  • CrossRef
  • Google Scholar

• 131

  ZhaoYXChenSRHuangQYChenWCXiaTShiYCet al. Repair Abilities of Mouse Autologous Adipose-Derived Stem Cells and ShakeGel3D Complex Local Injection With Intrauterine Adhesion by BMP7-Smad5 Signaling Pathway Activation. Stem Cell Res Ther (2021) 12:191. doi: 10.1186/s13287-021-02258-0

  • CrossRef
  • Google Scholar

• 132

  BraveryCACarmenJFongTOpreaWHoogendoornKHWodaJet al. Potency Assay Development for Cellular Therapy Products: An ISCT Review of the Requirements and Experiences in the Industry. Cytotherapy (2013) 15:9–19. doi: 10.1016/j.jcyt.2012.10.008

  • CrossRef
  • Google Scholar

• 133

  MeliefSMZwagingaJJFibbeWERoelofsH. Adipose Tissue-Derived Multipotent Stromal Cells Have a Higher Immunomodulatory Capacity Than Their Bone Marrow-Derived Counterparts. Stem Cells Trans Med (2013) 2:455–63. doi: 10.5966/sctm.2012-0184

  • CrossRef
  • Google Scholar

• 134

  ChanSHawleyCMCampbellKLMorrisonMCampbellSBIsbelNMet al. Transplant Associated Infections-The Role of the Gastrointestinal Microbiota and Potential Therapeutic Options. Nephrol (Carlton) (2020) 25:5–13. doi: 10.1111/nep.13670

  • CrossRef
  • Google Scholar

• 135

  ReindersMEde FijterJWRoelofsHBajemaIMde VriesDKSchaapherderAFet al. Autologous Bone Marrow-Derived Mesenchymal Stromal Cells for the Treatment of Allograft Rejection After Renal Transplantation: Results of a Phase I Study. Stem Cells Trans Med (2013) 2:107–11. doi: 10.5966/sctm.2012-0114

  • CrossRef
  • Google Scholar

• 136

  WangLTLiuKJSytwuHKYenMLYenBL. Advances in Mesenchymal Stem Cell Therapy for Immune and Inflammatory Diseases: Use of Cell-Free Products and Human Pluripotent Stem Cell-Derived Mesenchymal Stem Cells. Stem Cells Trans Med (2021) 10:1288–303. doi: 10.1002/sctm.21-0021

  • CrossRef
  • Google Scholar