Adult human stem/progenitor cells from bone marrow modulate stem and progenitor cells in the central nervous system
Description
Human adult stem/progenitor cells from bone marrow stroma (MSCs) modultate stem and progenitor cells in the central nervous system. Human MSCs were grown with rat neural stem cells (NSCs) in vitro. Direct coculture of the cells stimulated astrocyte and oligodendrocyte differentiation whereas MSC conditioned medium promoted only the oligodendroglial fate. Microarray analysis was used to survey changes in the transcriptomes of both cell types. NSCs grown in direct coculture with MSCs up-regulated transcripts associated with glial development. NSCs and MSCs up-regulated genes for signaling factors and component proteins in TGFb and Notch signaling pathways. NSCs expressed TGFb receptor 1, and coculture with MSCs increased TGFb secretion by MSCs. Blocking TGFb receptor 1 signaling attenuated the increase in glial differentiation. NSCs and MSCs express Notch ligands and receptors. Coculture increased Notch signaling and downstream transcription factors that drive astrocyte determination in NSCs. Blocking TGFb receptor 1 signaling attenuated the increase in Notch signaling in NSCs. MSCs also modulate rat oligodendrocyte progenitor cells (OPCs) in vitro and in an animal model of demyelination. MSCs injected into the rodent brain induced with a demyelinated lesion migrated toward the lesion and spared myelin loss. Surrounding the lesion MSCs reduced reactive astrocyte activation and stimulated proliferation and maturation of resident OPCs. In vitro MSC conditioned medium increased proliferation of immature OPCs whereas direct coculture additionally stimulated their maturation. Microarray analysis indicated OPCs grown in direct coculture up-regulated transcripts for mature oligodendrocyte proteins, and both cell types up-regulated genes for secreted factors and component proteins in signaling pathways. In vitro and in the demyelinated brain, MSCs secreted TGFb3 and OPCs expressed TGFb receptor 1. OPCs secreted IGF2 in vitro and coculture with MSCs increased IGF2 production. MSCs injection into the demyelinated brain increased IGF2 production by endogenous cells including OPCs. Coculture with MSCs stimulated OPC maturation and blocking IGF2 signaling attenuated the effect