Heterotypic Cell-Cell Interactions in Hybrid Human Stem Cell Microtissues during Neural Differentiation



 DESCRIPTION (provided by applicant): Despite the promising results from stem cell therapy in spinal cord injury, mesenchymal stem cells (MSCs) present an intermediate solution with short in vivo life span. Neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (hiPSCs) provide an alternative source for novel cell therapy, but the engraftment of hiPSC-NPCs needs to be improved. The formation of microtissues of hiPSC-NPCs and MSCs could up-regulate the secretion of trophic factors from MSCs and NPCs, and the secretion of anti-apoptotic and anti-inflammatory factors from MSCs to enhance NPC engraftment at injury site. However, the complex heterotypic interactions of MSCs with hiPSC-NPCs and their secretory activities during neurogenesis have not been well understood.} The objective of this proposal is to construct 3-D microtissues composed of human MSCs and hiPSC-derived NPCs, and investigate the impact of heterotypic cell-cell interactions on the secretion of extracellular matrices and trophic factors during neural differentiation in vitro. The central hypothesis is that the heterotypic cell-cell interactions and the secretion of endogenous extracellular matrices are modulated by the structure of microtissues of MSCs and hiPSC- derived NPCs which promote trophic factor section and functional neural differentiation. Specifically, the following aims are proposed: 1) Aim 1 will test the hypothesis that the composition and structure of microtissues differentially regulates the secretion of trophic factors, NPC differentiation, and cell survival under oxidative stress. 2) Aim 2 will test the hypothesis that the structure of microtissues regulates the secretion of endogenous ECMs to stimulate neurogenesis. {Neural microtissue self-assembly from hiPSCs in vitro was chosen by Science's editors as a runner-up for 2013 Breakthrough of the Year. By their unique ability to coordinate the dictatorial signals and to form tissue or mini-organ like structures reminiscent of cell organization in vivo, hiPSCs and their derivatives provide a novel platform to advance our understanding on tissue morphogenesis for the treatment of neurological disorders. The most innovative feature of this project is to evaluate microtissue-based neural differentiation by fabricating hybrid MSC-NPC microtissues with tunable structure to achieve the enhanced cellular function and neurogenesis. If successful, the proposed study will advance our understanding on the actions of hiPSC-derived NPCs and MSCs in treating neural injury and on the modulation of extracellular microenvironment during neurogenesis.