Recognition of cellular implants by the brain’s innate immune system
Peter
Ponsaerts1*,
Irene
Bergwerf1,
Nathalie
De Vocht1, 2,
Bart
Tambuyzer1,
Kristien
Reekmanns1,
Jelle
Praet1, 2,
Jasmijn
Daans1,
Patrick
Pauwels3,
Annemie
V.
Linden2 and
Zwi
Berneman1
-
1
University of Antwerp, Laboratory of Experimental Hematology, Belgium
-
2
University of Antwerp, BioImaging Laboratory, Belgium
-
3
University of Antwerp, Laboratory of Pathology, Belgium
Background
Cell transplantation is increasingly suggested to play an important role in future regenerative medicine aiming to restore injured or diseased neural tissue. Although several pre-clinical studies have demonstrated modest contribution of grafted (stem) cells to neuro-regeneration, there is still large controversy regarding their actual contribution, i.e. either by direct (functional) integration into target tissue or by displaying a (cytokine-secreting) neuro-protective role. Given the complexity of the CNS architecture itself and the active immune-surveillance of the CNS by microglia, our work aims to understand how the brain’s innate immune system accepts and/or rejects autologous and allogeneic cellular implants.
Methods
Murine bone marrow-derived mesenchymal stem cells (MSC) and embryonic (E14) brain-derived neural stem cells (NSC) were cultured from FVB-Luciferase transgenic mice and further genetically engineered with the eGFP reporter gene. Following transplantation in non-injured CNS of syngeneic FVB mice and allogeneic BALB/c mice, cell survival was monitored pre-mortem using in vivo bioluminescence imaging (BLI, luciferase reporter gene) and post-mortem by histological analysis (eGFP reporter gene). Additional histological analysis: (1) for MSC and NSC-specific markers (respectively Sca1 and GFAP in combination with eGFP) confirmed cell graft identity, (2) for different immune cell markers confirmed the presence or absence of Iba1+CD11b+/- microglia, CD4+ or CD8+ T-cells and NK-cells surrounding or infiltrating cell grafts, and (3) for GFAP+ astrocytes confirmed the presence or absence of endogenous astrocytic scar tissue surrounding or infiltrating cell grafts. Finally, ex vivo ELISPOT assay was performed to identify allograft-specific T-cell responses in the CNS.
Results
Autologous transplantation of MSC resulted in graft survival of at least 4 weeks as demonstrated by in vivo BLI and histological analysis. However, MSC grafts became highly infiltrated by Iba1+CD11b- microglia and encapsulated by GFAP+ astrocytic scar tissue. Allogeneic transplantation of MSC resulted in graft rejection from on 2 weeks post-transplantation as demonstrated by in vivo BLI and histological analysis. The immune-based rejection of MSC allografts was solely mediated by highly activated Iba1+CD11b+ microglia without involvement of T-cells and NK-cells, as demonstrated by histological analysis and ex vivo ELISPOT analysis. Autologous transplantation of NSC resulted in graft survival of 2 weeks followed by a progressive decrease in graft survival as monitored by in vivo BLI. Histological analysis further confirmed that NSC grafts became highly infiltrated by endogenous Iba1+CD11b- microglia and GFAP+ astrocytes.
Conclusion
Although the CNS has historically been considered to be immune-privileged, our data demonstrate that the CNS is not immune-ignorant to both autologous and allogeneic cellular implants. Therefore, further research in order to understand - and eventually deviate - the brain’s innate immune system will be of utmost importance in order to achieve successful neuro-engineering with cellular implants.
Keywords:
neuroengineering
Conference:
The Monte Verita' Workshop on the Frontiers in Neuroengineering, Ascona, Switzerland, 5 Sep - 9 Sep, 2010.
Presentation Type:
Oral Presentation
Topic:
Frontiers in Neuroengineering
Citation:
Ponsaerts
P,
Bergwerf
I,
De Vocht
N,
Tambuyzer
B,
Reekmanns
K,
Praet
J,
Daans
J,
Pauwels
P,
Linden
AV and
Berneman
Z
(2010). Recognition of cellular implants by the brain’s innate immune system.
Front. Neuroeng.
Conference Abstract:
The Monte Verita' Workshop on the Frontiers in Neuroengineering.
doi: 10.3389/conf.fneng.2010.10.00014
Copyright:
The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers.
They are made available through the Frontiers publishing platform as a service to conference organizers and presenters.
The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated.
Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed.
For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions.
Received:
18 Aug 2010;
Published Online:
10 Sep 2010.
*
Correspondence:
Dr. Peter Ponsaerts, University of Antwerp, Laboratory of Experimental Hematology, Antwerp, Belgium, peter.ponsaerts@ua.ac.be