Engineering temporal transitions in matrix environment to regulate hematopoietic stem cell activity
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1
University of Illinois at Urbana Champaign, Chemical and Biomolecular Engineering, United States
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2
University of Illinois at Urbana Champaign, Carl R. Woese Institute for Genomic Biology, United States
Introduction: The bone marrow provides a complex set of extrinsic signals that regulate hematopoietic stem cell (HSC) behavior, notably the production of the body’s full complement of blood and immune cells. An artificial marrow would have significant value for expanding HSCs or to study the onset and treatment of hematologic diseases. However, the influence of matrix biophysical properties and cell-cell interactions on HSC fate specification remains poorly understood. Here we describe a 3D methacrylamide-functionalized gelatin (GelMA) hydrogel capable of presenting multiple instructive cues that affect HSC quiescence vs. activation.
Materials and Methods: Stem cell factor (SCF), a cytokine known to promote HSC survival and proliferation was conjugated to a PEG acrylate chain, then immobilized within the GelMA hydrogel via photopolymerization. The viability and differentiation state of primary murine HSC were monitored over 7 days in variants of the GelMA-SCF construct. Subsequently, HSC phenotype in response to co-culture with murine marrow-derived mesenchymal stem cells (MSCs) as well as MSC-mediated matrix remodeling were traced over 14 days via changes in matrix diffusivity as well as HSC surface antigen expression and colony forming unit expression metrics.
Results and Discussion: While soluble SCF promotes HSC proliferation it comes at the expense of lineage specification. Selective inclusion of matrix-immobilized SCF promotes improved retention of primitive HSCs within the matrix[1] (Fig. 1).
Ongoing efforts are examining optimization of soluble and matrix bound SCF to promote expansion of primitive HSCs. HSC fate specification in the presence of MSCs was observed to depend on both initial density of MSCs and on MSC-mediated GelMA matrix remodeling. While MSC-mediated remodeling was limited in initially soft 5 wt% GelMA hydrogels at multiple HSC:MSC densities (1:1 to 1:10 HSC:MSC), remodeling was significantly enhanced in denser 7.5 wt% GelMA hydrogels. Interestingly, HSC were better maintained in lower gel density hydrogels and at lower HSC:MSC ratios (1:1), suggesting strategies to control not only initial hydrogel conditions but also niche cell mediated remodeling may be important for engineering HSC fate specification events (Fig. 2).
Conclusions: We have demonstrated a GelMA hydrogel platform to selectively promote maintenance of primitive HSC progenitors. Early results with MSC co-culture suggests cell-mediated matrix remodeling may also affect HSC biology. Ongoing efforts are working to characterize regulatory features of HSC-MSC co-cultures in order to better regulate early HSC fate decisions ex vivo.
References:
[1] Mahadik, B.P., et al., The use of covalently immobilized stem cell factor to selectively affect hematopoietic stem cell activity within a gelatin hydrogel. Biomaterials, 2015. 67: p. 297-307.
Keywords:
Hydrogel,
stem cell,
matrix-cell interaction,
instructive microenvironment
Conference:
10th World Biomaterials Congress, Montréal, Canada, 17 May - 22 May, 2016.
Presentation Type:
Poster
Topic:
Biomaterials in mesenchymal and hematopoietic stem cell biology
Citation:
Mahadik
B,
Harley
B and
Pedron Haba
S
(2016). Engineering temporal transitions in matrix environment to regulate hematopoietic stem cell activity.
Front. Bioeng. Biotechnol.
Conference Abstract:
10th World Biomaterials Congress.
doi: 10.3389/conf.FBIOE.2016.01.00534
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Received:
27 Mar 2016;
Published Online:
30 Mar 2016.