Project 1:  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.

Project 2:  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.

Project 3:  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 on 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.

Current Lab Members

David Miller
Med Student

David is a second-year med student. He is a participant of the NIH Summer Research Traineeships for Medical Students. He is studying ectopic expression of Nex1 on embryonic stem cell differentiation.

Collaborators

Theodore Cummins (IUSM Pharmacology & Toxicology)
Gerry Oxford (IUSM Pharmacology & Toxicology)
Rajesh Khanna (IUSM Pharmacology & Toxicology)
Edward Srour (IUSM Medicine)
Rebecca Chan (IUSM Pediatrics)
Navin Bansel (IUSM Radiology)
Jason Meyer (IUPUI Biology)

Raymond Romand (IGBMC, France)
Pascal Dolle (IGBMC, France)
Stephane Viville (IGBMC, France)
Josef Miller (Univ. Michigan)

Previous Members

Paul Chestovich
Med student (03)