Sonic hedgehog and retinoic acid synergistically promote sensory fate specification from bone marrow-derived pluripotent stem cells.
Recent studies demonstrated that stromal cells isolated from adult bone marrow have the competence of differentiating into neuronal cells in vitro and in vivo. However, the capacity of marrow stromal cells or mesenchymal stem cells (MSCs) to differentiate into diverse neuronal cell populations and the identity of molecular factors that confer marrow stromal cells with the competence of a neuronal subtype have yet to be elucidated. Here, we show that Sonic hedgehog (Shh) and retinoic acid (RA), signaling molecules secreted from tissues in the vicinity of peripheral sensory ganglia during embryogenesis, exert synergistic effects on neural-competent MSCs to express a comprehensive set of glutamatergic sensory neuron markers. Application of Shh or RA alone had little or no effect on the expression of these neuronal subtype markers. In addition, incubation of MSCs with embryonic hindbrain/somite/otocyst conditioned medium or prenatal cochlea explants promoted up-regulation of additional sensory neuron markers and process outgrowth. These results identify Shh and RA as sensory competence factors for adult pluripotent cells and establish the importance of interactions between adult pluripotent cells and the host microenvironment in neuronal subtype specification.
Kondo
Takako
T
Department of Otolaryngology-Head and Neck Surgery, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Johnson
Scott A
SA
Yoder
Mervin C
MC
Romand
Raymond
R
Hashino
Eri
E
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D005576:Colforsin; D017931:DNA Primers; D004357:Drug Synergism; D016222:Fibroblast Growth Factor 2; D005434:Flow Cytometry; D016147:Genes, Tumor Suppressor; D053823:Hedgehog Proteins; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009925:Organ of Corti / Q000166:cytology / Q000378:metabolism; D000072079:Patched Receptors; D039904:Pluripotent Stem Cells / Q000378:metabolism / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000072086:Smoothened Receptor; D015534:Trans-Activators / Q000378:metabolism / Q000494:pharmacology*; D014212:Tretinoin / Q000378:metabolism / Q000494:pharmacology*
D017931:DNA Primers; D053823:Hedgehog Proteins; D008565:Membrane Proteins; D000072079:Patched Receptors; C000607072:Rara protein, mouse; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; C465570:Shh protein, mouse; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D015534:Trans-Activators; D016222:Fibroblast Growth Factor 2; D005576:Colforsin; D014212:Tretinoin