Mesenchymal Stem Cells Instruct Oligodendrogenic Fate Decision on Adult Neural Stem Cells

TLDR

Adult stem cells include bone‑marrow mesenchymal stem cells (MSCs) and central‑nervous‑system neural stem cells (NSCs), but the mechanisms governing their interactions remain largely unknown. The study aims to show that soluble‑factor–mediated interactions between MSCs and NSCs drive NSCs toward oligodendrogenesis at the expense of astrogenesis. A candidate factor screen ruled out known growth factors, cytokines, and neurotrophins, indicating that MSC‑derived oligodendrogenic activity is mediated by yet‑unidentified soluble factors. MSC‑NSC co‑culture increased oligodendrocyte markers GalC and MBP, reduced GFAP, upregulated Olig1/2 and Nkx2.2 while downregulating Id2, and pulse‑labeling and fate analyses confirmed an inductive, not selective, mechanism, suggesting potential for CNS regenerative therapies.

Abstract

Adult stem cells reside in different tissues and organs of the adult organism. Among these cells are MSCs that are located in the adult bone marrow and NSCs that exist in the adult central nervous system (CNS). In transplantation experiments, MSCs demonstrated neuroprotective and neuroregenerative effects that were associated with functional improvements. The underlying mechanisms are largely unidentified. Here, we reveal that the interactions between adult MSCs and NSCs, mediated by soluble factors, induce oligodendrogenic fate decision in NSCs at the expense of astrogenesis. This was demonstrated (a) by an increase in the percentage of cells expressing the oligodendrocyte markers GalC and myelin basic protein, (b) by a reduction in the percentage of glial fibrillary acidic protein (GFAP)-expressing cells, and (c) by the expression pattern of cell fate determinants specific for oligodendrogenic differentiation. Thus, it involved enhanced expression of the oligodendrogenic transcription factors Olig1, Olig2, and Nkx2.2 and diminished expression of Id2, an inhibitor of oligodendrogenic differentiation. Results of (a) 5-bromo-2'-deoxyuridine pulse-labeling of cells, (b) cell fate analysis, and (c) cell death/survival analysis suggested an inductive mechanism and excluded a selection process. A candidate factor screen excluded a number of growth factors, cytokines, and neurotrophins that have previously been shown to influence neurogenesis and neural differentiation from the oligodendrogenic activity derived from the MSCs. This work might have major implications for the development of future transplantation strategies for the treatment of degenerative diseases in the CNS.