Microenvironment Regulation of Pluripotent Stem Cell-Derived Neural Progenitor Aggregates by Human Mesenchymal Stem Cell Secretome

Neural progenitor cells (NPCs) derived from pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced PSCs, are promising cell source for the treatment of various neurological diseases. NPC derivation from PSCs is regulated by microenvironment factors that influence cell fate via paracrine and autocrine effects. In this study, ESC-derived NPC aggregates were replated in the secretomes of bone marrow-derived human mesenchymal stem cells (hMSCs) generated under hypoxia or normoxia to investigate the effects of hMSC secretome on NPC cellular behaviors. The results demonstrated that hMSC secretomes stimulated endogenous secretion of extracellular matrices from NPC aggregates and enhanced cell adhesion and proliferation. NPC functional differentiation measured by migration length, neurite extension, and the yield of neural and glial cells were also increased by threefold to fourfold. Inhibition of fibroblast growth factor-2, transforming growth factor-beta 1, and brain-derived neurotrophic factor signaling differentially reduced the adherent cell number, migration length, and neurite extension, suggesting the regulatory effects of a broad spectrum of hMSC-derived factors. In summary, ESC-derived NPC aggregates in hypoxic hMSC secretomes may represent a suitable combination to promote the engraftment and neurogenesis in vivo.