Mesenchymal stem cells expressing neural antigens instruct a neurogenic cell fate on neural stem cells.
The neurogenic response to injury in the postnatal brain is limited and insufficient for restoration of function. Recent evidence suggests that transplantation of mesenchymal stem cells (MSCs) into the injured brain is associated with improved functional recovery, mediated in part through amplification in the endogenous neurogenic response to injury. In the current study we investigate the interactions between bone marrow-derived MSCs and embryonic neural stem cells (NSCs) plus their differentiated progeny using an in vitro co-culture system. Two populations of MSCs were used, MSCs induced to express neural antigens (nestin+, Tuj-1+, GFAP+) and neural antigen negative MSCs. Following co-culture of induced MSCs with differentiating NSC/progenitor cells a significant increase in Tuj-1+ neurons was detected compared to co-cultures of non-induced MSCs in which an increase in astrocyte (GFAP+) differentiation was observed. The effect was mediated by soluble interactions between the two cell populations and was independent of any effect on cell death and proliferation. Induced and non-induced MSCs also promoted the survival of Tuj-1+ cell progeny in long-term cultures and both promoted axonal growth, an effect also seen in differentiating neuroblastoma cells. Therefore, MSCs provide instructive signals that are able to direct the differentiation of NSCs and promote axonal development in neuronal progeny. The data indicates that the nature of MSC derived signals is dependent not only on their microenvironment but on the developmental status of the MSCs. Pre-manipulation of MSCs prior to transplantation in vivo may be an effective means of enhancing the endogenous neurogenic response to injury.
Croft
Adam P
AP
School of Biological and Biomedical Sciences, Durham University, South Road, Durham DH1 3LE, UK.
Przyborski
Stefan A
SA
D000704:Analysis of Variance; D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D018920:Coculture Techniques / Q000379:methods; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004622:Embryo, Mammalian; D005434:Flow Cytometry; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D007381:Intermediate Filament Proteins / Q000276:immunology / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000737:chemistry / Q000276:immunology*; D009419:Nerve Tissue Proteins / Q000276:immunology / Q000378:metabolism; D064231:Nestin; D016501:Neurites / Q000502:physiology; D055495:Neurogenesis / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D011419:Propidium / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D013997:Time Factors; D014404:Tubulin / Q000378:metabolism
D017077:Culture Media, Conditioned; D005904:Glial Fibrillary Acidic Protein; D036341:Intercellular Signaling Peptides and Proteins; D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; C577486:Nes protein, rat; D064231:Nestin; D014404:Tubulin; D011419:Propidium; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D001973:Bromodeoxyuridine