title: Systematic optimization of an engineered hydrogel allows for selective control of human neural stem cell survival and differentiation after transplantation in the stroke brain.
abstract: Stem cell therapies have shown promise in promoting recovery in stroke but have been limited by poor cell survival and differentiation. We have developed a hyaluronic acid (HA)-based self-polymerizing hydrogel that serves as a platform for adhesion of structural motifs and a depot release for growth factors to promote transplant stem cell survival and differentiation. We took an iterative approach in optimizing the complex combination of mechanical, biochemical and biological properties of an HA cell scaffold. First, we optimized stiffness for a minimal reaction of adjacent brain to the transplant. Next hydrogel crosslinkers sensitive to matrix metalloproteinases (MMP) were incorporated as they promoted vascularization. Finally, candidate adhesion motifs and growth factors were systemically changed in vitro using a design of experiment approach to optimize stem cell survival or proliferation. The optimized HA hydrogel, tested in vivo, promoted survival of encapsulated human neural progenitor cells (iPS-NPCs) after transplantation into the stroke core and differentially tuned transplanted cell fate through the promotion of glial, neuronal or immature/progenitor states. This HA hydrogel can be tracked in vivo with MRI. A hydrogel can serve as a therapeutic adjunct in a stem cell therapy through selective control of stem cell survival and differentiation in vivo.
authors: Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, 635 Charles Young Drive, CA 90095, USA.
authors: Pouria
authors: P
authors: Moshayedi
authors: Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, 420 Westwood Plaza, CA 90095, USA.
authors: Lina R
authors: LR
authors: Nih
authors: Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, 635 Charles Young Drive, CA 90095, USA.
authors: Irene L
authors: IL
authors: Llorente
authors: Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, 635 Charles Young Drive, CA 90095, USA.
authors: Andrew R
authors: AR
authors: Berg
authors: Department of Molecular Cell and Developmental Biology, University of California, Los Angeles, 710 Westwood Plaza, CA 90095, USA.
authors: Jessica
authors: J
authors: Cinkornpumin
authors: Department of Molecular Cell and Developmental Biology, University of California, Los Angeles, 710 Westwood Plaza, CA 90095, USA.
authors: William E
authors: WE
authors: Lowry
authors: Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, 420 Westwood Plaza, CA 90095, USA. Electronic address: tsegura@g.ucla.edu.
authors: Tatiana
authors: T
authors: Segura
authors: Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, 635 Charles Young Drive, CA 90095, USA. Electronic address: scarmichael@mednet.ucla.edu.
authors: S Thomas
authors: ST
authors: Carmichael
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology* / Q000601:surgery; D002454:Cell Differentiation; D002470:Cell Survival; D002478:Cells, Cultured; D048091:Guided Tissue Regeneration / Q000295:instrumentation; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry; D020100:Hydrogels / Q000737:chemistry*; D008297:Male; D008422:Materials Testing; D051379:Mice; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000166:cytology* / Q000637:transplantation*; D033581:Stem Cell Transplantation / Q000295:instrumentation / Q000379:methods; D020521:Stroke / Q000473:pathology* / Q000628:therapy*; D013499:Surface Properties; D013718:Tensile Strength; D054457:Tissue Scaffolds; D016896:Treatment Outcome; D014783:Viscosity
chemical_list: D020100:Hydrogels; D006820:Hyaluronic Acid
keywords: Angiogenesis; Astrocyte; Hyaluronan; Neural stem cell; Regeneration; iPS