Neuroectodermally converted human mesenchymal stromal cells provide cytoprotective effects on neural stem cells and inhibit their glial differentiation

Abstract

Background aims: In recent years, bone marrow (BM)-derived mesenchymal stromal cells (MSC) have become a promising source for neuroregenerative therapies. We evaluated the trophic effects of neuroectodermally converted MSC (mNSC) on neural stem cells (NSC).

Methods: We quantified the expression of growth factors by mNSC using real-time reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) and studied the effects of mNSC conditioned medium and mNSC (in direct co-culture) on NSC proliferation, differentiation and survival.

Results: Neuroectodermal conversion of human MSC induced high expression of growth factors at both mRNA and protein levels, most prominently hepatocyte growth factor, vascular endothelial growth factor and amphiregulin (37 +/- 17, 92 +/- 44 and 12 +/- 11 ng/10(5) cells, respectively), which remained at high levels upon co-culturing with neural cells. Accordingly, mNSC conditioned medium and co-cultivation with mNSC reduced cell death of NSC (36% of control), stimulated their proliferation, attenuated glial differentiation of NSC (7 +/- 3 versus 59 +/- 6%; P < 0.01) and protected NSC against the neurotoxin 6-hydroxydopamine (with half-maximally concentrations EC(50) values of 217 +/- 207 microM in the presence of mNSC compared with 62 +/- 49 microM for NSC alone).

Conclusions: mNSC promote survival and proliferation, and inhibit glial differentiation, of NSC. Protection of NSC by mNSC against 6-hydroxy-dopamine is probably mediated by the release of cytotrophic factors. Our results promote neuroectodermally converted MSC as promising candidate cells for the development of neuroregenerative and neuroprotective therapies.