Enhancing neural stem cell response to SDF-1α gradients through hyaluronic acid-laminin hydrogels.
Traumatic brain injury (TBI) initiates an expansive biochemical insult that is largely responsible for the long-term dysfunction associated with TBI; however, current clinical treatments fall short of addressing these underlying sequelae. Pre-clinical investigations have used stem cell transplantation with moderate success, but are plagued by staggeringly low survival and engraftment rates (2-4%). As such, providing cell transplants with the means to better dynamically respond to injury-related signals within the transplant microenvironment may afford improved transplantation survival and engraftment rates. The chemokine stromal cell-derived factor-1α (SDF-1α) is a potent chemotactic signal that is readily present after TBI. In this study, we sought to develop a transplantation vehicle to ultimately enhance the responsiveness of neural transplants to injury-induced SDF-1α. Specifically, we hypothesize that a hyaluronic acid (HA) and laminin (Lm) hydrogel would promote 1. upregulated expression of the SDF-1α receptor CXCR4 in neural progenitor/stem cells (NPSCs) and 2. enhanced NPSC migration in response to SDF-1α gradients. We demonstrated successful development of a HA-Lm hydrogel and utilized standard protein and cellular assays to probe NPSC CXCR4 expression and NPSC chemotactic migration. The findings demonstrated that NPSCs significantly increased CXCR4 expression after 48 h of culture on the HA-Lm gel in a manner critically dependent on both HA and laminin. Moreover, the HA-Lm hydrogel significantly increased NPSC chemotactic migration in response to SDF-1α at 48 h, an effect that was critically dependent on HA, laminin and the SDF-1α gradient. Therefore, this hydrogel serves to 1. prime NPSCs for the injury microenvironment and 2. provide the appropriate infrastructure to support migration into the surrounding tissue, equipping cells with the tools to more effectively respond to the injury microenvironment.
School of Biological and Health Systems Engineering, Arizona State University, P.O. Box 879709, Tempe, AZ 85287-9709, USA.
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Addington
School of Biological and Health Systems Engineering, Arizona State University, P.O. Box 879709, Tempe, AZ 85287-9709, USA; Barrow Brain Tumor Research Center, Barrow Neurological Institute, 350 W Thomas Road, Phoenix, AZ 85013, USA.
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JM
Heffernan
School of Biological and Health Systems Engineering, Arizona State University, P.O. Box 879709, Tempe, AZ 85287-9709, USA.
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CS
Millar-Haskell
School of Biological and Health Systems Engineering, Arizona State University, P.O. Box 879709, Tempe, AZ 85287-9709, USA.
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EW
Tucker
School of Biological and Health Systems Engineering, Arizona State University, P.O. Box 879709, Tempe, AZ 85287-9709, USA; Barrow Brain Tumor Research Center, Barrow Neurological Institute, 350 W Thomas Road, Phoenix, AZ 85013, USA.
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RW
Sirianni
School of Biological and Health Systems Engineering, Arizona State University, P.O. Box 879709, Tempe, AZ 85287-9709, USA. Electronic address: sarah.stabenfeldt@asu.edu.
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Stabenfeldt
D000818:Animals; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000494:pharmacology*; D002633:Chemotaxis / Q000187:drug effects; D006820:Hyaluronic Acid / Q000494:pharmacology*; D020100:Hydrogels / Q000494:pharmacology*; D007797:Laminin / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D054377:Chemokine CXCL12; D020100:Hydrogels; D007797:Laminin; D019718:Receptors, CXCR4; D006820:Hyaluronic Acid
Brain injury; Chemotaxis; Regenerative medicine; SDF-1α-CXCR4 axis; Tissue engineering