Eri Hashino, Ph.D.
Ruth C. Holton Professor of Otolaryngology-HNS
Professor of Anatomy and Cell Biology; and Pharmacology and Toxicology
Ph.D., Nagoya University (1991)
Neural Differentiation from Embryonic and Somatic Stem Cells.
Research in my lab investigates the mechanisms by which cell-intrinsic transcription factors and extracellular signals cooperatively instruct pluripotent stem cells to differentiate into neurons bearing phenotypic and functional properties of inner ear sensory neurons. Since the vast majority of these sensory neurons use glutamate as a primary neurotransmitter, my lab has been primarily focusing on identifying factors that promote glutamatergic neuronal specification during stem cell differentiation. In order to assess both in vitro and in vivo functional properties of stem cell-derived neurons exhibiting a glutamatergic phenotype, my lab, in collaboration with other on-campus investigators, is taking interdisciplinary approaches, including cellular/molecular biology, biochemistry, cellular electrophysiology and imaging, MRI and animal models.
Epigenetic regulation of neuronal differentiation from pluripotent stem cells: T cell leukemia 3 (Tlx3) is a member of the Tlx family of homeobox transcription factors and is selectively expressed in cranial sensory ganglia, including spiral ganglion neurons (SGNs), during early embryogenesis. We recently found that Tlx3 promotes selective activation of glutamatergic marker genes, which is accompanied by enhanced post-synaptic transmission, in mouse embryonic stem cells (ESCs) only after these cells are committed to a neural lineage. These results demonstrate that Tlx3 is a context-dependent fate selector that confers ESC-derived neurons with a glutamatergic neurotransmitter phenotype. The primary goals of this study are (1) to elucidate the epigenetic mechanisms underlying context-dependent functions of Tlx3 on neuronal subtype specification, and (2) to assess both in vitro and in vivo properties of ESC-derived neurons expressing Tlx3.
Somatic stem cells as delivery vectors for inner ear therapy: The goal of this project is to establish and validate a robust, safe and long-lasting delivery method using somatic stem cells as vectors to transport biologically active molecules into the inner ear. Somatic stem cells, such as mesenchymal stem cells (MSCs) and induced pluripotent stem cells (iPSCs), represent a promising source of material for autologous cell transplantation therapies. While these stem cells can be used to replace damaged cells in the inner ear, our recent study has demonstrated that transplanted somatic stem cells exhibit remarkable abilities to identify and migrate towards damaged spiral ganglion neurons in the inner ear. This property makes somatic stem cells a unique tool to deliver therapeutic agents selectively to damaged cells in the inner ear. We are currently establishing stem cell lines stably expressing high-level BDNF. These stem cells releasing BDNF will be transplanted into the cochlea of an animal model of auditory neuropathy. Migration and engraftment of these stem cells will be monitored by a high-resolution microscopic-endoscope-based imaging system and MRI.
Modeling neurodegenerative disorders using patient-derived induced pluripotent stem cells: In collaboration with Dr. Jason Meyer (IUPUI Biology), we are establishing iPSCs derived from patients suffering from Type I Usher Syndrome. Usher Syndrome is the most frequent cause of hereditary deaf-blindness in humans. It is characterized by severe to profound congenital hearing impairment, vestibular dysfunction and progressive retinitis pigmentosa. However, the molecular mechanisms underlying the auditory and visual impairment are poorly understood. We are making progress in generating Usher Syndrome patient-derived iPSCs, which will be then cultivated to differentiate into sensory hair cells in the inner ear and photo receptor cells in the retina. These stem cell-derived hair cells and retinal cells will harbor the same genome predisposed to Usher Syndrome, and thus serve as a potent model system to investigate disease-specific pathogenesis and potential phenotypic rescue.
Kondo T, Matsuoka AJ, Shimomura A, Koehler KR, Chan RJ, Miller JM, Srour EF, Hashino E. (2011) Wnt signaling promotes neuronal differentiation from somatic pluripotent stem cells through activation of Tlx3. Stem Cells 29: 836-846.
Hashino E, Fritsch MH (2011) Embryonic stem cell-derived neurons for inner ear therapy. In: C. Atwood (Ed.), Embryonic Stem Cells - Recent Advances in Pluripotent Stem Cell-Based Regenerative Medicine, INTECH, Rijeka, Croatia, pp.189-202.
Ma P, Vemula S, Munugalavadla V, Chen J, Sims E, Borneo J, Kondo T, Mali RS, Ramdas B, Li S, Hashino E, Takemoto C, Kapur R (2011) Balanced interactions between Lyn, p85α regulatory subunit of class IA phosphatidylinositol-3-kinase and SHIP is essential for mast cell growth and maturation. Mol. Cell. Biol. (In Press)
Koehler KR, Tropel P, Thiele JW, Kondo T, Cummins TR, Viville S, Hashino E. (2011) Extended passaging increases efficiency of neural differentiation from induced pluripotent stem cells. BMC Neuroscience. (In Press)
Yang Z, Kondo T, Voorhorst CS, Nabinger SC, Ndong L, Yin F, Chan EM, Niemeyer CM, Kratz CP, Flotho C, Hashino E, Chan RJ (2009) Increased c-Jun and reduced GATA2 promotes aberrant monocytic differentiation induced by activating PTPN11 mutants. Mol. Cell Biol. 29: 4376-4393.
Kondo T, Sheets PL, Zopf DA, Aloor HL, Cummins TR, Chan RJ, Hashino E. (2008) Tlx3 exerts context-dependent transcriptional regulation and promotes neuronal differentiation from embryonic stem cells. Proc. Natl. Acad. Sci. USA 105: 5780-5785.
Romand R, Kondo T, Cammas L, Hashino E, Dolle P (2008) Dynamic expression of the retinoic acid-synthesizing enzyme retinol dehydrogenase 10 (RDH10) in the developing mouse brain and sensory organs. J. Comp. Neurol. 508: 879-892.
Kondo T, Johnson SA, Yoder MC, Romand R, Hashino E. (2005) Sonic hedgehog and retinoic acid synergistically promote sensory fate specification from bone marrow-derived pluripotent stem cells. Proc. Natl. Acad. Sci. USA 102: 4789-4794.
Romand R, Krezel W, Fraulob V, Messaddeq N, Kessler P, Bianchetti L, Cammas L, Hashino E, Dolle P (2011) Retinoic acid deficiency impairs the vestibular function (Submitted).