Sonic hedgehog and retinoic acid synergistically promote sensory fate specification from bone marrow-derived pluripotent stem cells

Kondo, Takako; Johnson, Scott A.; Yöder, Mervin C.; Romand, R.; Hashino, Eri

doi:10.1073/pnas.0408239102

Cited by 164 publications

(124 citation statements)

References 36 publications

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“…If genetic manipulation to introduce Tlx3 in ES cells accompanies any risks to the human health, then we would need to identify a signaling protein that promotes Tlx3 expression. We previously demonstrated that a conditioned medium prepared from the E10 mouse hindbrain/somite/otocyst can up-regulate Ngn1, NeuroD, Brn3a, GluR4, and VGLUT2-the same set of genes upregulated in ES cell-derived neurons by Tlx3-in adult pluripotent progenitor cells after neural induction (21). Interestingly, Tlx3 expression was also induced in these neural competent progenitor cells grown in the hindbrain/somite/otocyst conditioned medium (T.K., unpublished observations).…”

Section: Discussionmentioning

confidence: 99%

Tlx3 exerts context-dependent transcriptional regulation and promotes neuronal differentiation from embryonic stem cells

Kondo¹,

Sheets

Zopf³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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The T cell leukemia 3 (Tlx3) gene has been implicated in specification of glutamatergic sensory neurons in the spinal cord. In cranial sensory ganglia, Tlx3 is highly expressed in differentiating neurons during early embryogenesis. To study a role of Tlx3 during neural differentiation, mouse embryonic stem (ES) cells were transfected with a Tlx3 expression vector. ES cells stably expressing Tlx3 were grown in the presence or absence of a neural induction medium. In undifferentiated ES cells, there was no significant difference in gene expression in the presence or absence of Tlx3, even after ES cells were cultured for an extensive time period. In contrast, expression levels of Mash1, Ngn1, and NeuroD were significantly higher in Tlx3-expressing cells after neural induction for 4 days compared with those in cells expressing the control vector. At 7 days after neural induction, whereas expression of the proneural genes was down-regulated, VGLUT2, GluR2, and GluR4 were significantly increased in ES cellderived neurons expressing Tlx3. The sequential and coordinated expression of the proneural and neuronal subtype-specific genes identifies Tlx3 as a selector gene in ES cells undergoing neural differentiation. In addition, the differential effects of Tlx3 overexpression in undifferentiated ES cells compared with ES cell-derived neurons suggest that Tlx3 exerts context-dependent transcriptional signals on its downstream target genes. The context-dependent function of Tlx3 as a selector gene may be used to establish a novel strategy to conditionally generate excitatory glutamatergic neurons from ES cells to cure various types of neurodegenerative disorders.glutamatergic neurons ͉ mouse ͉ proneural genes ͉ sensory ganglia

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Section: Discussionmentioning

confidence: 99%

Tlx3 exerts context-dependent transcriptional regulation and promotes neuronal differentiation from embryonic stem cells

Kondo¹,

Sheets

Zopf³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…Potential cell sources for inner ear transplantation include fetal dorsal root ganglion cells (Hu et al 2004;Regala et al 2005), neural progenitor cells (Ito et al 2001;Corrales et al 2006;), stem or progenitor cells isolated from inner ear (Li et al 2003a;Doetzlhofer et al 2004;Rask-Andersen et al 2005;Zhai et al 2005), immortalized auditory neuroblast cells (Nicholl et al 2005;Liu et al 2006a, b), ESCs and their derived neuronal cells (Li et al 2003b;Hu et al 2004Hu et al , 2005Hildebrand et al 2006;Okano et al 2005;Regala et al 2005;Coleman et al 2006;Sakamoto et al 2004;Sekiya et al 2006;Corrales et al 2006), and marrow stromal cells treated with sonic hedgehog and retinoic acid (Kondo et al 2005). ESCs derived from the inner cell mass of the blastocyst are capable of undergoing an unlimited number of divisions and differentiating into cell types of all three germ layers.…”

Section: Introductionmentioning

confidence: 99%

Transplantation of Mouse Embryonic Stem Cells into the Cochlea of an Auditory-Neuropathy Animal Model: Effects of Timing after Injury

Lang

Schulte

Goddard

et al. 2008

JARO

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Application of ouabain to the round window membrane of the gerbil selectively induces the death of most spiral ganglion neurons and thus provides an excellent model for investigating the survival and differentiation of embryonic stem cells (ESCs) introduced into the inner ear. In this study, mouse ESCs were pretreated with a neural-induction protocol and transplanted into Rosenthal's canal (RC), perilymph, or endolymph of Mongolian gerbils either 1-3 days (early post-injury transplant group) or 7 days or longer (late post-injury transplant group) after ouabain injury. Overall, ESC survival in RC and perilymphatic spaces was significantly greater in the early post-injury microenvironment as compared to the later post-injury condition. Viable clusters of ESCs within RC and perilymphatic spaces appeared to be associated with neovascularization in the early post-injury group. A small number of ESCs transplanted within RC stained for mature neuronal or glial cell markers. ESCs introduced into perilymph survived in several locations, but most differentiated into glia-like cells. ESCs transplanted into endolymph survived poorly if at all. These experiments demonstrate that there is an optimal time window for engraftment and survival of ESCs that occurs in the early post-injury period.

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“…This in vitro approach has also been applied to bone marrow derived stem cells. Kondo et al (2005) demonstrated sonic hedgehog and retinoic acid when in combination induced differentiation of marrow stromal cells to a neuronal phenotype with a greater than 200-fold increase in GATA3, Irx2, Sox10, calretinin and GluR4 mRNAs (all expressed during normal development in auditory nerve neurons) and Wnt 1 induced a 400-fold increase in the expression level of Brn3a, Ngn2 (neuroD) and Ngn1, which play a role in the differentiation of auditory neurons during normal development. Falk et al (2002) found that transduction of stem cells with Neurogenin 2 (Ngn2) induced over 90% towards a neuronal phenotype.…”

Section: Differentiation Into An Appropriate Phenotypementioning

confidence: 99%

Stem cell transplantation for auditory nerve replacement

2008

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The successful function of cochlear prostheses depends on activation of auditory nerve. The survival of auditory nerve neurons, however, can vary widely in candidates for cochlear implants and influence implant efficacy. Stem cells offer the potential for improving the function of cochlear prostheses and increasing the candidate pool by replacing lost auditory nerve. The first phase of studies for stem cell replacement of auditory nerve has examined the in vitro survival and differentiation as well as in vivo differentiation and survival of exogenous embryonic and tissue stem cells placed into scala tympani and/or modiolus. These studies are reviewed and new results on in vivo placement of B-5 mouse embryonic stem cells into scala tympani of the guinea pig cochleae with differentiation into a glutamatergic neuronal phenotype are presented. Research on the integration and connections of stem cell derived neurons in the cochlea is described. Finally, an alternative approach is considered, based on the use of endogenous progenitors rather than exogenous stem cells, with a review of promising findings that have identified stem cell-like progenitors in cochlear and vestibular tissues to provide the potential for auditory nerve replacement.

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Sonic hedgehog and retinoic acid synergistically promote sensory fate specification from bone marrow-derived pluripotent stem cells

Cited by 164 publications

References 36 publications

Tlx3 exerts context-dependent transcriptional regulation and promotes neuronal differentiation from embryonic stem cells

Tlx3 exerts context-dependent transcriptional regulation and promotes neuronal differentiation from embryonic stem cells

Transplantation of Mouse Embryonic Stem Cells into the Cochlea of an Auditory-Neuropathy Animal Model: Effects of Timing after Injury

Stem cell transplantation for auditory nerve replacement

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