Stefan Heller

Honors and Awards

• McKnight Neuroscience of Brain Disorders Award, McKnight Endowment Fund for Neuroscience (2005-2007)
• Burt Evans Young Investigator Award, National Organization for Hearing Research Foundation (2005)
• Albert and Ellen Grass Faculty Grant Award, Marine Biological Laboratory, Woods Hole, MA (Summer 2004, Summer 2005)
• Franklin M. Rizer Lectureship, The American Neurotology Society (2004)
• Basil O'Connor Starter Scholar Research Award, March of Dimes (2001-2003)
• Juergen Tonndorf Award, Deafness Research Foundation (2001)

Professional Education

• Postdoctoral Fellow, The Rockefeller University Sensory Neuroscience (2000)
• Dr rer nat (Ph.D.), Johannes Gutenberg University, Mainz, Germany Genetics (1994)
• Dipl Biol (M.S.), Johannes Gutenberg University, Mainz, Germany Biological Sciences (1990)

Postdoctoral Advisees

• Lars Becker, Zhaohua Guo, Meike Herget, Roman Laske, Kazuo Oshima

Graduate & Fellowship Program Affiliations

• Molecular and Cellular Physiology
• Neurosciences

Web Site Links

• Heller Lab Website

Industry Relationships

Stanford is committed to ethical and transparent interactions with our industry partners. It is our policy to disclose payments of $5,000 or more, equity valued at $5,000 or more in a publicly traded company, or any equity in a privately held company, to physicians and scientists employed by Stanford University from companies or other commercial entities with which they interact as part of their professional activities. 

• Consulting: Otonomy, Inc
• Equity: Otonomy, Inc

Research Interests

Current Lines of Research:

All hearing sensation is derived from the electrical output of a remarkably small number of sensory cells: fewer that 15,000 per cochlea. These hair cells are the mechanoelectrical transducers of the inner ear: deflections of the stereociliary bundles on their apical surfaces lead to transmitter release from their basolateral poles, leading, in turn, to signal generation in the peripheral axons of the auditory nerve fibers.

Most types of congenital and acquired hearing loss arise from loss of these sensory cells. The incidence of heritable deafness is high: one child in a thousand is born deaf; another one in a thousand becomes deaf before adulthood. The prevalence of acquired hearing loss is rising, as the population ages, and as noise pollution steadily increases. It is estimated that one in three adults over the age of 65 has a handicapping hearing loss.

Underlying the irreversibility of hearing loss in mammals is the incapacity to replace lost hair cells by cell division or by regeneration from endogenous cells in the inner ear epithelia. Hair cell replacement, either by stimulation of regeneration (as occurs naturally in non-mammalian vertebrates) or by transplantation of progenitor cells capable of differentiating into hair cells, remains therefore the ultimate goal in the development of treatment applications to reconstruct the damaged inner ear.

Our recent work has focused on creating inner ear cell types, in particular hair cells and auditory neurons, from a renewable source. We have shown that embryonic stem (ES) cells and somatic inner ear stem cells can serve as such a source. The ongoing research in my laboratory is focusing on defining and exploring signaling pathways that control hair cell and auditory neuronal generation in vitro and in vivo toward a better understanding of native inner ear development and, ultimately, to develop cell- or drug-based therapies for inner ear disorders.

A second emerging line of research focuses on functional characterization of genes and proteins that are involved in hair cell mechanotransduction or stereociliary function. The long-term goal of this research is to unravel the structure and function of the mechanoelectrical transduction machinery, a multi-protein complex located at the tips of stereocilia. This research involves molecular, biochemical, and biophysical approaches as well as structural biology.

Publications

• Life and death of sensory hair cells expressing constitutively active TRPML3. Grimm C,  Jörs S, Heller S.  J Biol Chem.  2009; 284 (20): 13823-31
• Differentiation of neurons from neural precursors generated in floating spheres from embryonic stem cells. Li H,  Liu H, Corrales CE, Risner JR, Forrester J, Holt JR, Heller S, Edge AS.  BMC Neurosci.  2009; 10 122
• Isolation of sphere-forming stem cells from the mouse inner ear. Oshima K,  Senn P, Heller S.  Methods Mol Biol.  2009; 493 141-62
• Stem/progenitor cells derived from the cochlear sensory epithelium give rise to spheres with distinct morphologies and features. Diensthuber M,  Oshima K, Heller S.  J Assoc Res Otolaryngol.  2009; 10 (2): 173-90
• Rethinking how hearing happens. Xu Z,  Ricci AJ, Heller S.  Neuron.  2009; 62 (3): 305-7
• Quo vadis, hair cell regeneration? Brigande JV,  Heller S.  Nat Neurosci.  2009; 12 (6): 679-85
• Diverse expression patterns of LIM-homeodomain transcription factors (LIM-HDs) in mammalian inner ear development. Huang M,  Sage C, Li H, Xiang M, Heller S, Chen ZY.  Dev Dyn.  2008; 237 (11): 3305-12
• MAGI-1, a candidate stereociliary scaffolding protein, associates with the tip-link component cadherin 23. Xu Z,  Peng AW, Oshima K, Heller S.  J Neurosci.  2008; 28 (44): 11269-76
• Transient receptor potential vanilloid 4 deficiency suppresses unloading-induced bone loss. Mizoguchi F,  Mizuno A, Hayata T, Nakashima K, Heller S, Ushida T, Sokabe M, Miyasaka N, Suzuki M, Ezura Y, Noda M.  J Cell Physiol.  2008; 216 (1): 47-53
• Stimulus-specific modulation of the cation channel TRPV4 by PACSIN 3. D'hoedt D,  Owsianik G, Prenen J, Cuajungco MP, Grimm C, Heller S, Voets T, Nilius B.  J Biol Chem.  2008; 283 (10): 6272-80
• [Stem-cell-based approaches for treating inner ear diseases] Senn P,  Heller S.  HNO.  2008; 56 (1): 21-6
• LIF promotes neurogenesis and maintains neural precursors in cell populations derived from spiral ganglion stem cells. Oshima K,  Teo DT, Senn P, Starlinger V, Heller S.  BMC Dev Biol.  2007; 7 112
• Differential distribution of stem cells in the auditory and vestibular organs of the inner ear. Oshima K,  Grimm CM, Corrales CE, Senn P, Martinez Monedero R, Géléoc GS, Edge A, Holt JR, Heller S.  J Assoc Res Otolaryngol.  2007; 8 (1): 18-31
• Bone marrow mesenchymal stem cells are progenitors in vitro for inner ear hair cells. Jeon SJ,  Oshima K, Heller S, Edge AS.  Mol Cell Neurosci.  2007; 34 (1): 59-68
• A helix-breaking mutation in TRPML3 leads to constitutive activity underlying deafness in the varitint-waddler mouse. Grimm C,  Cuajungco MP, van Aken AF, Schnee M, Jörs S, Kros CJ, Ricci AJ, Heller S.  Proc Natl Acad Sci U S A.  2007; 104 (49): 19583-8
• Robust postmortem survival of murine vestibular and cochlear stem cells. Senn P,  Oshima K, Teo D, Grimm C, Heller S.  J Assoc Res Otolaryngol.  2007; 8 (2): 194-204
• The potential role of endogenous stem cells in regeneration of the inner ear. Martinez-Monedero R,  Oshima K, Heller S, Edge AS.  Hear Res.  2007; 227 (1-2): 48-52
• Dual role of the TRPV4 channel as a sensor of flow and osmolality in renal epithelial cells. Wu L,  Gao X, Brown RC, Heller S, O'Neil RG.  Am J Physiol Renal Physiol.  2007; 293 (5): F1699-713
• TRP channels as candidates for hearing and balance abnormalities in vertebrates. Cuajungco MP,  Grimm C, Heller S.  Biochim Biophys Acta.  2007; 1772 (8): 1022-7
• Engraftment and differentiation of embryonic stem cell-derived neural progenitor cells in the cochlear nerve trunk: growth of processes into the organ of Corti. Corrales CE,  Pan L, Li H, Liberman MC, Heller S, Edge AS.  J Neurobiol.  2006; 66 (13): 1489-500
• Sonic hedgehog promotes mouse inner ear progenitor cell proliferation and hair cell generation in vitro. Zhao Y,  Wang Y, Wang Z, Liu H, Shen Y, Li W, Heller S, Li H.  Neuroreport.  2006; 17 (2): 121-4
• Generation of inner ear cell types from embryonic stem cells. Rivolta MN,  Li H, Heller S.  Methods Mol Biol.  2006; 330 71-92
• PACSINs bind to the TRPV4 cation channel. PACSIN 3 modulates the subcellular localization of TRPV4. Cuajungco MP,  Grimm C, Oshima K, D'hoedt D, Nilius B, Mensenkamp AR, Bindels RJ, Plomann M, Heller S.  J Biol Chem.  2006; 281 (27): 18753-62
• Reinnervation of hair cells by auditory neurons after selective removal of spiral ganglion neurons. Martinez-Monedero R,  Corrales CE, Cuajungco MP, Heller S, Edge AS.  J Neurobiol.  2006; 66 (4): 319-31
• Sound from silence. Oshima K,  Heller S.  Nat Med.  2005; 11 (3): 249-50
• Identification of chicken transmembrane channel-like (TMC) genes: expression analysis in the cochlea. Mutai H,  Mann S, Heller S.  Neuroscience.  2005; 132 (4): 1115-22
• BMP4 signaling is involved in the generation of inner ear sensory epithelia. Li H,  Corrales CE, Wang Z, Zhao Y, Wang Y, Liu H, Heller S.  BMC Dev Biol.  2005; 5 16
• The mechanosensitive nature of TRPV channels. O'Neil RG,  Heller S.  Pflugers Arch.  2005; 451 (1): 193-203
• Islet-1 expression in the developing chicken inner ear. Li H,  Liu H, Sage C, Huang M, Chen ZY, Heller S.  J Comp Neurol.  2004; 477 (1): 1-10
• Stem cells as therapy for hearing loss. Li H,  Corrales CE, Edge A, Heller S.  Trends Mol Med.  2004; 10 (7): 309-15
• Correlation of Pax-2 expression with cell proliferation in the developing chicken inner ear. Li H,  Liu H, Corrales CE, Mutai H, Heller S.  J Neurobiol.  2004; 60 (1): 61-70
• Absence of the RGS9.Gbeta5 GTPase-activating complex in photoreceptors of the R9AP knockout mouse. Keresztes G,  Martemyanov KA, Krispel CM, Mutai H, Yoo PJ, Maison SF, Burns ME, Arshavsky VY, Heller S.  J Biol Chem.  2004; 279 (3): 1581-4
• Correlation of expression of the actin filament-bundling protein espin with stereociliary bundle formation in the developing inner ear. Li H,  Liu H, Balt S, Mann S, Corrales CE, Heller S.  J Comp Neurol.  2004; 468 (1): 125-34
• Vertebrate and invertebrate TRPV-like mechanoreceptors. Mutai H,  Heller S.  Cell Calcium.  2003 May-Jun; 33 (5-6): 471-8
• TMC and EVER genes belong to a larger novel family, the TMC gene family encoding transmembrane proteins. Keresztes G,  Mutai H, Heller S.  BMC Genomics.  2003; 4 (1): 24
• The DEP domain determines subcellular targeting of the GTPase activating protein RGS9 in vivo. Martemyanov KA,  Lishko PV, Calero N, Keresztes G, Sokolov M, Strissel KJ, Leskov IB, Hopp JA, Kolesnikov AV, Chen CK, Lem J, Heller S, Burns ME, Arshavsky VY.  J Neurosci.  2003; 23 (32): 10175-81
• Generation of hair cells by stepwise differentiation of embryonic stem cells. Li H,  Roblin G, Liu H, Heller S.  Proc Natl Acad Sci U S A.  2003; 100 (23): 13495-500
• Expression of Frizzled genes in the developing chick eye. Fuhrmann S,  Stark MR, Heller S.  Gene Expr Patterns.  2003; 3 (5): 659-62
• Pluripotent stem cells from the adult mouse inner ear. Li H,  Liu H, Heller S.  Nat Med.  2003; 9 (10): 1293-9
• Expression patterns of the RGS9-1 anchoring protein R9AP in the chicken and mouse suggest multiple roles in the nervous system. Keresztes G,  Mutai H, Hibino H, Hudspeth AJ, Heller S.  Mol Cell Neurosci.  2003; 24 (3): 687-95
• Application of physiological genomics to the study of hearing disorders. Heller S,  J Physiol.  2002; 543 (Pt 1): 3-12
• A unified nomenclature for the superfamily of TRP cation channels. Montell C,  Birnbaumer L, Flockerzi V, Bindels RJ, Bruford EA, Caterina MJ, Clapham DE, Harteneck C, Heller S, Julius D, Kojima I, Mori Y, Penner R, Prawitt D, Scharenberg AM, Schultz G, Shimizu N, Zhu MX.  Mol Cell.  2002; 9 (2): 229-31
• Molecular screens for inner ear genes. Heller S,  J Neurobiol.  2002; 53 (2): 265-75
• Parvalbumin 3 is an abundant Ca2+ buffer in hair cells. Heller S,  Bell AM, Denis CS, Choe Y, Hudspeth AJ.  J Assoc Res Otolaryngol.  2002; 3 (4): 488-98
• Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor. Liedtke W,  Choe Y, Martí-Renom MA, Bell AM, Denis CS, Sali A, Hudspeth AJ, Friedman JM, Heller S.  Cell.  2000; 103 (3): 525-35
• A novel conserved cochlear gene, OTOR: identification, expression analysis, and chromosomal mapping. Robertson NG,  Heller S, Lin JS, Resendes BL, Weremowicz S, Denis CS, Bell AM, Hudspeth AJ, Morton CC.  Genomics.  2000; 66 (3): 242-8
• Mutations in a novel cochlear gene cause DFNA9, a human nonsyndromic deafness with vestibular dysfunction. Robertson NG,  Lu L, Heller S, Merchant SN, Eavey RD, McKenna M, Nadol JB, Miyamoto RT, Linthicum FH, Lubianca Neto JF, Hudspeth AJ, Seidman CE, Morton CC, Seidman JG.  Nat Genet.  1998; 20 (3): 299-303
• Differential regulation of ciliary neurotrophic factor receptor-alpha expression in all major neuronal cell classes during development of the chick retina. Fuhrmann S,  Kirsch M, Heller S, Rohrer H, Hofmann HD.  J Comp Neurol.  1998; 400 (2): 244-54
• Molecular markers for cell types of the inner ear and candidate genes for hearing disorders. Heller S,  Sheane CA, Javed Z, Hudspeth AJ.  Proc Natl Acad Sci U S A.  1998; 95 (19): 11400-5
• The specification of sympathetic neurotransmitter phenotype depends on gp130 cytokine receptor signaling. Geissen M,  Heller S, Pennica D, Ernsberger U, Rohrer H.  Development.  1998; 125 (23): 4791-801
• A transient role for ciliary neurotrophic factor in chick photoreceptor development. Fuhrmann S,  Heller S, Rohrer H, Hofmann HD.  J Neurobiol.  1998; 37 (4): 672-83
• Two deaf mice, two deaf mice... Heller S,  Hudspeth AJ.  Nat Med.  1998; 4 (5): 560-1
• Onset of CNTFRalpha expression and signal transduction during neurogenesis in chick sensory dorsal root ganglia. Holst A,  Heller S, Junghans D, Geissen M, Ernsberger U, Rohrer H.  Dev Biol.  1997; 191 (1): 1-13
• Distribution of Ca2+-activated K+ channel isoforms along the tonotopic gradient of the chicken's cochlea. Rosenblatt KP,  Sun ZP, Heller S, Hudspeth AJ.  Neuron.  1997; 19 (5): 1061-75
• Extrinsic signals in the developing nervous system: the role of neurokines during neurogenesis. Heller S,  Ernsberger U, Rohrer H.  Perspect Dev Neurobiol.  1996; 4 (1): 19-34
• Analysis of function and expression of the chick GPA receptor (GPAR alpha) suggests multiple roles in neuronal development. Heller S,  Finn TP, Huber J, Nishi R, Geissen M, Püschel AW, Rohrer H.  Development.  1995; 121 (8): 2681-93
• GPA and CNTF produce similar effects in sympathetic neurones but differ in receptor binding. Heller S,  Huber J, Finn TP, Nishi R, Rohrer H.  Neuroreport.  1993; 5 (3): 357-60
• Bioluminescence-based detection of genetically engineered microorganisms in nonsterile river water. Heller S,  Bühler S, Kilz S, Mieschendahl M.  Microb Releases.  1992; 1 (1): 35-9