Systematic optimization of an engineered hydrogel allows for selective control of human neural stem cell survival and differentiation after transplantation in the stroke brain.

Pouria Moshayedi,Lina R Nih,Andrew R Berg,Jessica Cinkornpumin,S Thomas Carmichael,Irene L Llorente,Tatiana Segura,William E Lowry

doi:10.1016/j.biomaterials.2016.07.028

Pouria Moshayedi, Lina R Nih + Show 6 more

Open Access

https://doi.org/10.1016/j.biomaterials.2016.07.028

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Journal: Biomaterials	Publication Date: Aug 2, 2016
Citations: 233	License type: cc-by

Affiliation: University of California, Los Angeles

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 invitro using a design of experiment approach to optimize stem cell survival or proliferation. The optimized HA hydrogel, tested invivo, 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 invivo with MRI. A hydrogel can serve as a therapeutic adjunct in a stem cell therapy through selective control of stem cell survival and differentiation invivo.

Highlights

Stroke is the leading cause of long-term disability [1]
We have previously reported a hyaluronic acid hydrogel crosslinked in situ via thiol/acrylate Michael type addition for human induced pluripotent neural precursor culture in vitro, which demonstrated biocompatibility after transplantation in vivo [13]
hyaluronic acid (HA) gels with three different stiffness levels 100, 350 and 1000 Pa were injected in the stroke cavity (Figure 1A, 1Bi-iii) one week after the stroke onset

Summary

Introduction

Stroke is the leading cause of long-term disability [1]. There are no therapies that promote recovery in this disease. New strategies aimed at enhancing post-stroke brain plasticity have utilized trophic factors, stem cell therapies or a combination of the two. Their clinical translation has been limited because of the short half-life and undesirable systemic effects of injected growth factors [2, 3] and poor survival of transplanted cells [4], partly due to the abrupt withdrawal of adhesive support and the inflammatory environment of the damaged brain [5]. The lack of a successful medical therapy that promotes long-term recovery in stroke imposes a substantial clinical and economic burden, indicating the need for a novel therapeutic solution

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