Our laboratory works on inner ear development and regeneration, as well as on the biology of sensory hair cells, the mechanosensitive cells of the inner ear. We are located at Stanford University in the School of Medicine and affiliated with the Otolaryngology department. We are proudly affiliated with the Stanford Initiative to Cure Hearing Loss and we thank all supporters of this endeavor.
We are interested how the inner ear develops from an early anlage called the otic placode. Our goal is to describe the otic lineage from an early placodal progenitor until it splits up in multiple cell types making up the sensory epithelia, innervating ganglia, and accessory structures.
In parallel, we apply knowledge we gained from guiding embryonic and induced pluripotent stem cells along the otic lineage to find ways for treatment of hearing loss. This involves identification of mechanisms of sensory hair cell regeneration in animals such as chickens that recover naturally from hearing loss, screening for potential regenerative targets that can be activated with drugs, and exploring reprograming as well as cell transplantation strategies.
The image shown above depicts the embryonic mouse inner ear stained with an antibody to a protein that is specifically expressed in the otic lineage. Postdoctoral fellow Byron Hartman is working on this ongoing project and provided this spectacular image.
We are actively looking for a postdoctoral fellow to join our group in 2016. The successful candidate should have a strong interest in solving open questions how fate decisions in the developing and regenerating inner ear are being orchestrated. We expect strong work ethics, creativity, and ability to independently learn and implement new technologies. Interest in computational analysis methods of single cell transcriptome data is a requirement.
If you are interested in joining our group, please send a single introductory paragraph and your CV to Stefan Heller at firstname.lastname@example.org
• Waldhaus, J.,Durruthy-Durruthy, R. & Heller, S. Quantitative High-Resolution Cellular Map of the Organ of Corti. Cell Reports 11:9 June (2015). http://www.cell.com/cell-reports/abstract/S2211-1247(15)00494-5
It is my opinion that this paper has the potential for a landmark paper in our field and beyond. First, it clearly shows that single cell gene expression analysis and bioinformatic reconstruction methods are very precise and robust, therefore providing a credible tool for functional and mechanistic analyses. We will definitely use this technology in coming years to explore cellular and molecular mechanisms that regulate development and possibly also regeneration. Second, the data shown in this paper clearly demonstrate that conventional in situ hybridizations are a method of the past – good bye in situs! We initially submitted the manuscript to Neuron where it received one highly constructive review and two reviews indicating that the reviewers were not convinced of the robustness of our methods. Neuron suggested to move the manuscript to their open-access partner journal Cell Reports. There, the editor asked us to respond to the critiques raised in the Neuron reviews and the revised paper was accepted. Beside the high publication cost (5K!), Cell Reports seems to be a reasonable journal – proofing and dealing with the production crew was a breeze, probably also because I was out of town and Jörg and Robert took care of dealing with this process ;-). Congratulations to both for this fine piece of work!
• Maass, J.C., Gu, R., Basch, M.L., Waldhaus, J., Martin Lopez, E., Xia, A., Oghalai, J.S., Heller, S. & Groves, A.K. Changes in the Regulation of the Notch Signaling Pathway are Temporally Correlated with Regenerative Failure in the Mouse Cochlea. Frontiers in Cellular Neuroscience 9:110 (2015). http://journal.frontiersin.org/article/10.3389/fncel.2015.00110/abstract
Our lab contributed to this paper quantitative single cell measurements of Notch pathway gene expression in the young (P2) and juvenile (P21) mouse cochlea. What we found supports the main conclusion of the paper that the previously reported loss of responsiveness to inhibition of the Notch pathway in mice is likely explainable (at least in part) by down-regulation of Notch receptors, ligands and effectors. It does not exclude the Notch pathway as a therapeutic target for hair cell regeneration on mammals, but it suggests that other pathways might have to be targeted either simultaneously or before Notch inhibition.
• Hartman, B.H., Durruthy-Durruthy, R., Laske, R.D., Losorelli, S. & Heller, S. Identification and Characterization of Mouse Otic Sensory Lineage Genes. Frontiers in Cellular Neuroscience 9:79 (2015). http://journal.frontiersin.org/article/10.3389/fncel.2015.00079/abstract
Byron discovered that much more specific genes exist that can be used as family exclusive markers of the optic lineage than previously thought. He used existing data from our lab published a few years ago and data generated by Roman Laske, a visiting M.D. from Switzerland and then went on to find that the Fbxo2 gene is specific and highly expressed in cells of the extended pro-sensory region of the cochlear floor that ultimately develop into the organ of Corti and into closely adjacent structures. The paper is our laboratory’s contribution to a series of inner ear papers in the Frontiers Journal. Thank you editors and reviewers for inviting us and for constructive reviews.
• Durruthy-Durruthy, R. & Heller, S. Applications for Single Cell Trajectory Analysis in Inner Ear Development and Regeneration. Cell and Tissue Research XXX, ??? (2015). http://www.ncbi.nlm.nih.gov/pubmed/25532874
This is an invited review that is not really extensive but it shows some of the limitations and directions of the emerging field of temporal transcriptomics. The development of novel and better bioinformatics analysis methods to order cells as they change their phenotype over time is going to be key to understand regenerative processes in the inner ear. There is lots of work to be done in this area in future years.
• Durruthy-Durruthy, R., Gottlieb, A. & Heller, S. 3D computational reconstruction of tissues with hollow spherical morphologies using single-cell gene expression data. Nature Protocols 10, 459-474 (2015). http://www.nature.com/nprot/journal/v10/n3/full/nprot.2015.022.html
This paper is a follow up on last year’s paper published in Cell. We were not able to provide detailed step-by-step instructions about the 3D reconstruction method in the original publication, but we thought that the method would be useful to others. 3 of the 4 reviewers agreed with this view, but it took a while to convince the fourth reviewer. If one follows the topics of the lab’s publications, there is an emerging theme of combining novel ideas for bioinformatics data analysis and visualization with important questions in inner ear biology. The current revolution of single cell transcriptomics is going to impact our field enormously.
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