Dr. Taha Jan graduated summa cum laude with a bachelor's in molecular and cellular biology with honors from Vanderbilt University. As an undergraduate, he worked in the laboratory of Dr. Larry Zwiebel on the olfactory system and in the laboratory of Dr. Robert Waters investigating the somatosensory cortex and gustatory system. He then attended medical school at Stanford University, where he studied the role of the Wnt pathway in murine cochlear development under the tutelage of Dr. Alan Cheng. He spent an extra year as a Howard Hughes Medical Institutes research fellow while at Stanford to further pursue his research interests on cochlear development, stem cell biology, and regenerative medicine.

Dr. Jan completed his internship in general surgery at the Mass General Hospital (MGH) and completed residency in Otolaryngology - Head & Neck Surgery in the Harvard/Mass Eye & Ear Infirmary training program in Boston. His work during residency focused on the effects of secreted factors from human vestibular schwannomas on hearing loss in the Eaton-Peabody Laboratories as part of Dr. Tina Stankovic?s group. During residency, he published on superior canal dehiscence etiology, endoscopic ear surgery techniques, and hearing loss. Dr. Jan is a current postdoctoral research fellow and ACGME otology/neurotology fellow in the Stanford T32 funded Clinician Scientist Training Program (CSTP). His research interests include development of the inner ear and stem cell biology with the goal of ultimately translating discoveries in these areas into therapeutics for patients suffering from hearing and vestibular disorders. His clinical interests include hearing loss, otosclerosis, stapes surgery, cholesteatoma, endoscopic ear surgery, cochlear implantation, tympanic membrane perforation, sudden sensorineural hearing loss, superior canal dehiscence syndrome, acoustic neuroma (vestibular schwannoma), temporal bone tumors.

Clinical Focus

  • Neurotology
  • Otology
  • Hearing Loss
  • Skull Base Surgery
  • Fellow

Boards, Advisory Committees, Professional Organizations

  • Diplomate, American Board of Otolaryngology - Head and Neck Surgery (2018 - Present)

Professional Education

  • Residency, Mass Eye & Ear Infirmary / Harvard Medical School, Otolaryngology - Head & Neck Surgery (2017)
  • Internship, Massachusetts General Hospital, General Surgery (2013)


All Publications

  • The future of otology. The Journal of laryngology and otology Jackler, R. K., Jan, T. A. 2019: 1?12


    The field of otology is increasingly at the forefront of innovation in science and medicine. The inner ear, one of the most challenging systems to study, has been rendered much more open to inquiry by recent developments in research methodology. Promising advances of potential clinical impact have occurred in recent years in biological fields such as auditory genetics, ototoxic chemoprevention and organ of Corti regeneration. The interface of the ear with digital technology to remediate hearing loss, or as a consumer device within an intelligent ecosystem of connected devices, is receiving enormous creative energy. Automation and artificial intelligence can enhance otological medical and surgical practice. Otology is poised to enter a new renaissance period, in which many previously untreatable ear diseases will yield to newly introduced therapies.This paper speculates on the direction otology will take in the coming decades.Making predictions about the future of otology is a risky endeavour. If the predictions are found wanting, it will likely be because of unforeseen revolutionary methods.

    View details for DOI 10.1017/S0022215119001531

    View details for PubMedID 31462337

  • Pneumatocele of the Tympanic Membrane. Otology & neurotology Gadkaree, S. K., Jan, T. A., Quesnel, A. M. 2017

    View details for DOI 10.1097/MAO.0000000000001363

    View details for PubMedID 28198720

  • Relationship between Surgically Treated Superior Canal Dehiscence Syndrome and Body Mass Index. Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery Jan, T. A., Cheng, Y. S., Landegger, L. D., Lin, B. M., Srikanth, P., Niesten, M. E., Lee, D. J. 2017: 194599816686563-?


    Objective Examine the association between body mass index (BMI) and superior canal dehiscence (SCD) among patients who have undergone surgical repair for superior canal dehiscence. Study Design Retrospective comparison study. Setting Neurotology tertiary care center. Subjects and Methods Retrospective review of consecutive adult patients evaluated at our institution for SCD syndrome between November 2006 and August 2015. A control group who underwent imaging within the same period for reasons other than SCD was also included. Patient demographics, weight, and height were examined. We performed multiple subgroup analyses to investigate the relationship of BMI, surgery vs no surgery, and correlation between patient BMI and SCD size. Results Of the 268 patients with SCD, 99 underwent surgery; 96 of these patients had complete medical records and were eligible for inclusion. Eighty-eight patients were noted to have arcuate eminence defects, and the mean BMI of this surgical cohort was 28.09 ± 5.26 kg/m(2). Nonsurgically treated patients with SCD with available data (n = 94) had a mean BMI of 27.97 ± 6.95 kg/m(2). A control group of 204 patients who underwent computed tomography for non-SCD-related causes was analyzed, of whom 155 had available data with a mean BMI of 27.91 ± 6.38 kg/m(2). Conclusion We demonstrate that adult patients who undergo surgery for SCD are not obese (mean BMI <30), and size of dehiscence poorly correlates with BMI. Our observations call into question the proposed theory that patient weight is a risk factor for the development of symptomatic SCD involving the arcuate eminence.

    View details for DOI 10.1177/0194599816686563

    View details for PubMedID 28116976

  • Third-generation bisphosphonates for cochlear otosclerosis stabilizes sensorineural hearing loss in long-term follow-up. Laryngoscope investigative otolaryngology Jan, T. A., Remenschneider, A. K., Halpin, C., Seton, M., McKenna, M. J., Quesnel, A. M. 2017; 2 (5): 262?68


    To assess long-term hearing outcomes in patients treated with third-generation bisphosphonates for otosclerosis-related progressive sensorineural hearing loss (SNHL).Retrospective case series review.We performed a retrospective case series review of patients with otosclerosis and progressive SNHL. Patients were treated with either risedronate or zoledronate after a diagnosis of otosclerosis with a significant SNHL component. Bone conduction pure tone threshold averages (BC-PTAs) and word recognition scores (WRS) before and after bisphosphonate administration in long-term follow-up was analyzed. Significant change in BC-PTA was defined as greater than 10dB or between 4% and 18% in WRS based on binomial variance.Seven patients were identified and 14 ears met inclusion criteria. Three patients were female and the mean age was 48.3?±?10.3 years. The mean duration between treatment with bisphosphonate administration and long-term post-treatment follow-up audiometry was 87.6?±?18.3 months, with a range of 61.6 to 109.1 months and median of 89.2 months. Analysis using BC-PTA and WRS demonstrated that 11 ears remained stable while 2 improved and 1 worsened. No patient experienced any major complication as the result of bisphosphonate therapy.Treatment with third-generation bisphosphonates is associated with stability in otosclerosis-related sensorineural hearing over 5- to 9-year period. These results suggest that such medications may prevent the progression of SNHL in patients with otosclerosis.4 (Case series).

    View details for DOI 10.1002/lio2.91

    View details for PubMedID 29094069

    View details for PubMedCentralID PMC5655565

  • Improvement in word recognition following treatment failure for sudden sensorineural hearing loss. World journal of otorhinolaryngology - head and neck surgery Jan, T. A., Kozin, E. D., Kanumuri, V. V., Sethi, R. K., Jung, D. H. 2016; 2 (3): 168?74


    Patients with sudden sensorineural hearing loss (SSNHL) may have word recognition scores (WRS) that correlate with pure tone average (PTA). We hypothesize that there is a subset of patients with SSNHL who have improved WRS despite stable PTA.Retrospective case review at a tertiary otolaryngology practice.We identified 13 of 113 patients with SSNHL whose WRS increased despite overall stable pure tone averages. There was an observed average improvement in WRS by 23.8 points in this patient cohort at follow-up, with mean initial PTA in the affected ear at 48.7 dB.We identify a novel cohort of SSNHL patients that have failed treatment as measured by PTA, but who have increased WRS over time. These data have implications for patient counseling and lend insight into the pathophysiology of SSNHL.

    View details for DOI 10.1016/j.wjorl.2016.06.002

    View details for PubMedID 29204563

    View details for PubMedCentralID PMC5698528

  • Profiling Specific Inner Ear Cell Types Using Cell Sorting Techniques. Methods in molecular biology (Clifton, N.J.) Jan, T. A., Jansson, L., Atkinson, P. J., Wang, T., Cheng, A. G. 2016; 1427: 431-445


    Studies of specific tissue cell types are becoming increasingly important in advancing our understanding of cell biology and gene and protein expression. Prospective isolation of specific cell types is a powerful technique as it facilitates such investigations, allowing for analysis and characterization of individual cell populations. Such an approach to studying inner ear tissues presents a unique challenge because of the paucity of cells of interest and limited cell markers. In this chapter, we describe methods for selectively labeling and isolating different inner ear cell types from the neonatal mouse cochlea using fluorescence-activated cell sorting.

    View details for DOI 10.1007/978-1-4939-3615-1_23

    View details for PubMedID 27259940

  • Skin Necrosis as a Complication of Therapeutic Hypothermia JOURNAL OF BURN CARE & RESEARCH Liu, Y. M., Ibrahim, A., Jan, T., Chang, P., Fagan, S., Goverman, J. 2014; 35 (3): E184-E186


    This case report describes a complication caused by cooling pads used for therapeutic hypothermic resuscitation. The authors hope to highlight and emphasize the importance of a thorough evaluation of all skin surfaces that are in direct contact with such cooling pads. Skin injury from the cooling pads used for therapeutic hypothermia should be recognized as a potential complication of treatment.

    View details for DOI 10.1097/BCR.0b013e3182a22730

    View details for Web of Science ID 000335394600008

    View details for PubMedID 24043239

  • Transient, afferent input-dependent, postnatal niche for neural progenitor cells in the cochlear nucleus. Proceedings of the National Academy of Sciences of the United States of America Volkenstein, S., Oshima, K., Sinkkonen, S. T., Corrales, C. E., Most, S. P., Chai, R., Jan, T. A., Cheng, A. G., Heller, S. 2013; 110 (35): 14456-14461


    In the cochlear nucleus (CN), the first central relay of the auditory pathway, the survival of neurons during the first weeks after birth depends on afferent innervation from the cochlea. Although input-dependent neuron survival has been extensively studied in the CN, neurogenesis has not been evaluated as a possible mechanism of postnatal plasticity. Here we show that new neurons are born in the CN during the critical period of postnatal plasticity. Coincidently, we found a population of neural progenitor cells that are controlled by a complex interplay of Wnt, Notch, and TGF?/BMP signaling, in which low levels of TGF?/BMP signaling are permissive for progenitor proliferation that is promoted by Wnt and Notch activation. We further show that cells with activated Wnt signaling reside in the CN and that these cells have high propensity for neurosphere formation. Cochlear ablation resulted in diminishment of progenitors and Wnt/?-catenin-active cells, suggesting that the neonatal CN maintains an afferent innervation-dependent population of progenitor cells that display active canonical Wnt signaling.

    View details for DOI 10.1073/pnas.1307376110

    View details for PubMedID 23940359

  • Intranasal myiasis: A rare complication of transnasal skull base surgery JOURNAL OF CLINICAL NEUROSCIENCE Jan, T. A., Redjal, N., Walcott, B. P., Sheth, S. A. 2013; 20 (8): 1178-1180


    A 57-year-old woman with a history of atypical intracranial meningioma had undergone multiple craniotomies and endoscopic skull base procedures over several years. She presented most recently with nasal discharge consisting of intranasal larvae. Isolated organisms from the nasal cavity and maxillary sinus were identified as blow fly larvae (Calliphoridae family). The patient was treated with transnasal debridement and antibiotic therapy. The organisms were successfully eradicated and she is free from further signs of infection. Intranasal myiasis is an unusual complication of anterior skull base surgery.

    View details for DOI 10.1016/j.jocn.2012.09.028

    View details for Web of Science ID 000322500300033

    View details for PubMedID 23669173

  • Tympanic border cells are Wnt-responsive and can act as progenitors for postnatal mouse cochlear cells DEVELOPMENT Jan, T. A., Chai, R., Sayyid, Z. N., van Amerongen, R., Xia, A., Wang, T., Sinkkonen, S. T., Zeng, Y. A., Levin, J. R., Heller, S., Nusse, R., Cheng, A. G. 2013; 140 (6): 1196-1206


    Permanent hearing loss is caused by the irreversible damage of cochlear sensory hair cells and nonsensory supporting cells. In the postnatal cochlea, the sensory epithelium is terminally differentiated, whereas tympanic border cells (TBCs) beneath the sensory epithelium are proliferative. The functions of TBCs are poorly characterized. Using an Axin2(lacZ) Wnt reporter mouse, we found transient but robust Wnt signaling and proliferation in TBCs during the first 3 postnatal weeks, when the number of TBCs decreases. In vivo lineage tracing shows that a subset of hair cells and supporting cells is derived postnatally from Axin2-expressing TBCs. In cochlear explants, Wnt agonists stimulated the proliferation of TBCs, whereas Wnt inhibitors suppressed it. In addition, purified Axin2(lacZ) cells were clonogenic and self-renewing in culture in a Wnt-dependent manner, and were able to differentiate into hair cell-like and supporting cell-like cells. Taken together, our data indicate that Axin2-positive TBCs are Wnt responsive and can act as precursors to sensory epithelial cells in the postnatal cochlea.

    View details for DOI 10.1242/dev.087528

    View details for Web of Science ID 000315445800006

    View details for PubMedID 23444352

    View details for PubMedCentralID PMC3585657

  • A simple method for purification of vestibular hair cells and non-sensory cells, and application for proteomic analysis. PloS one Herget, M., Scheibinger, M., Guo, Z., Jan, T. A., Adams, C. M., Cheng, A. G., Heller, S. 2013; 8 (6)


    Mechanosensitive hair cells and supporting cells comprise the sensory epithelia of the inner ear. The paucity of both cell types has hampered molecular and cell biological studies, which often require large quantities of purified cells. Here, we report a strategy allowing the enrichment of relatively pure populations of vestibular hair cells and non-sensory cells including supporting cells. We utilized specific uptake of fluorescent styryl dyes for labeling of hair cells. Enzymatic isolation and flow cytometry was used to generate pure populations of sensory hair cells and non-sensory cells. We applied mass spectrometry to perform a qualitative high-resolution analysis of the proteomic makeup of both the hair cell and non-sensory cell populations. Our conservative analysis identified more than 600 proteins with a false discovery rate of <3% at the protein level and <1% at the peptide level. Analysis of proteins exclusively detected in either population revealed 64 proteins that were specific to hair cells and 103 proteins that were only detectable in non-sensory cells. Statistical analyses extended these groups by 53 proteins that are strongly upregulated in hair cells versus non-sensory cells and vice versa by 68 proteins. Our results demonstrate that enzymatic dissociation of styryl dye-labeled sensory hair cells and non-sensory cells is a valid method to generate pure enough cell populations for flow cytometry and subsequent molecular analyses.

    View details for DOI 10.1371/journal.pone.0066026

    View details for PubMedID 23750277

    View details for PubMedCentralID PMC3672136

  • Effect of Obesity and Medical Comorbidities on Outcomes After Adjunct Surgery for Obstructive Sleep Apnea in Cases of Adenotonsillectomy Failure ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY Chan, D. K., Jan, T. A., Koltai, P. J. 2012; 138 (10): 891-896


    To evaluate the effect of body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) and medical comorbidities on outcomes after lingual tonsillectomy and supraglottoplasty performed for obstructive sleep apnea syndrome (OSAS) caused by lingual tonsillar hypertrophy and occult laryngomalacia.Retrospective case review seriesAcademic tertiary referral centerChildren with persistent OSAS after adenotonsillectomy who underwent surgery to correct obstruction at the level of the lingual tonsils and/or supraglottis identified on sleep endoscopy.All children underwent lingual tonsillectomy, supraglottoplasty, or both.Change in polysomnographic parameters, including apnea-hypopnea index (AHI), number of nighttime apneas, and lowest oxygen saturation level.We analyzed the medical records of 84 children with persistent OSAS after adenotonsillectomy who underwent either lingual tonsillectomy (n = 68), supraglottoplasty (n = 24) or both (n = 8). Compared with children with lingual tonsillar hypertrophy, children with occult laryngomalacia were younger, had lower BMI, and were more likely to have a medical comorbidity. Overall, both operations significantly improved the AHI; however, children with comorbidities had significantly higher postoperative AHIs after supraglottoplasty than those without, and overweight children had significantly higher postoperative AHIs after lingual tonsillectomy than those of normal weight. The BMI z-score and age had direct, though weak, correlations with postoperative AHI among all children undergoing either technique of adjunct airway surgery.Lingual tonsillar hypertrophy and occult laryngomalacia are 2 important causes of residual OSAS after adenotonsillectomy. However, they tend to affect distinct populations of children, and though appropriate surgical correction can improve AHI, cure rates are significantly worse for overweight children undergoing lingual tonsillectomy and for children with medical comorbidities undergoing supraglottoplasty.

    View details for Web of Science ID 000309916600001

    View details for PubMedID 23069817

  • Wnt signaling induces proliferation of sensory precursors in the postnatal mouse cochlea PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Chai, R., Kuo, B., Wang, T., Liaw, E. J., Xia, A., Jan, T. A., Liu, Z., Taketo, M. M., Oghalai, J. S., Nusse, R., Zuo, J., Cheng, A. G. 2012; 109 (21): 8167-8172


    Inner ear hair cells are specialized sensory cells essential for auditory function. Previous studies have shown that the sensory epithelium is postmitotic, but it harbors cells that can behave as progenitor cells in vitro, including the ability to form new hair cells. Lgr5, a Wnt target gene, marks distinct supporting cell types in the neonatal cochlea. Here, we tested the hypothesis that Lgr5(+) cells are Wnt-responsive sensory precursor cells. In contrast to their quiescent in vivo behavior, Lgr5(+) cells isolated by flow cytometry from neonatal Lgr5(EGFP-CreERT2/+) mice proliferated and formed clonal colonies. After 10 d in culture, new sensory cells formed and displayed specific hair cell markers (myo7a, calretinin, parvalbumin, myo6) and stereocilia-like structures expressing F-actin and espin. In comparison with other supporting cells, Lgr5(+) cells were enriched precursors to myo7a(+) cells, most of which formed without mitotic division. Treatment with Wnt agonists increased proliferation and colony-formation capacity. Conversely, small-molecule inhibitors of Wnt signaling suppressed proliferation without compromising the myo7a(+) cells formed by direct differentiation. In vivo lineage tracing supported the idea that Lgr5(+) cells give rise to myo7a(+) hair cells in the neonatal Lgr5(EGFP-CreERT2/+) cochlea. In addition, overexpression of ?-catenin initiated proliferation and led to transient expansion of Lgr5(+) cells within the cochlear sensory epithelium. These results suggest that Lgr5 marks sensory precursors and that Wnt signaling can promote their proliferation and provide mechanistic insights into Wnt-responsive progenitor cells during sensory organ development.

    View details for DOI 10.1073/pnas.1202774109

    View details for Web of Science ID 000304445800053

    View details for PubMedID 22562792

    View details for PubMedCentralID PMC3361451

  • Dynamic Expression of Lgr5, a Wnt Target Gene, in the Developing and Mature Mouse Cochlea JARO-JOURNAL OF THE ASSOCIATION FOR RESEARCH IN OTOLARYNGOLOGY Chai, R., Xia, A., Wang, T., Jan, T. A., Hayashi, T., Bermingham-McDonogh, O., Cheng, A. G. 2011; 12 (4): 455-469


    The Wnt signaling pathway is a recurring theme in tissue development and homeostasis. Its specific roles during inner ear development are just emerging, but few studies have characterized Wnt target genes. Lgr5, a member of the G protein-coupled receptor family, is a Wnt target in the gastrointestinal and integumentary systems. Although its function is unknown, its deficiency leads to perinatal lethality due to gastrointestinal distension. In this study, we used a knock-in reporter mouse to examine the spatiotemporal expression of Lgr5 in the cochlear duct during embryonic and postnatal periods. In the embryonic day 15.5 (E15.5) cochlear duct, Lgr5-EGFP is expressed in the floor epithelium and overlapped with the prosensory markers Sox2, Jagged1, and p27(Kip1). Nascent hair cells and supporting cells in the apical turn of the E18.5 cochlear duct express Lgr5-EGFP, which becomes downregulated in hair cells and subsets of supporting cells in more mature stages. In situ hybridization experiments validated the reporter expression, which gradually decreases until the second postnatal week. Only the third row of Deiters' cells expresses Lgr5-EGFP in the mature organ of Corti. Normal cochlear development was observed in Lgr5(EGFP/EGFP) and Lgr5(EGFP/+) mice, which exhibited normal auditory thresholds. The expression pattern of Lgr5 contrasts with another Wnt target gene, Axin2, a feedback inhibitor of the Wnt pathway. Robust Axin2 expression was found in cells surrounding the embryonic cochlear duct and becomes restricted to tympanic border cells below the basilar membrane in the postnatal cochlea. Both Lgr5 and Axin2 act as Wnt targets in the cochlea because purified Wnt3a promoted and Wnt antagonist suppressed their expression. Their differential expression among cell populations highlights the dynamic but complex distribution of Wnt-activated cells in and around the embryonic and postnatal cochlea.

    View details for DOI 10.1007/s10162-011-0267-2

    View details for Web of Science ID 000292047900004

    View details for PubMedID 21472479

    View details for PubMedCentralID PMC3123443

  • Intrinsic regenerative potential of murine cochlear supporting cells SCIENTIFIC REPORTS Sinkkonen, S. T., Chai, R., Jan, T. A., Hartman, B. H., Laske, R. D., Gahlen, F., Sinkkonen, W., Cheng, A. G., Oshima, K., Heller, S. 2011; 1


    The lack of cochlear regenerative potential is the main cause for the permanence of hearing loss. Albeit quiescent in vivo, dissociated non-sensory cells from the neonatal cochlea proliferate and show ability to generate hair cell-like cells in vitro. Only a few non-sensory cell-derived colonies, however, give rise to hair cell-like cells, suggesting that sensory progenitor cells are a subpopulation of proliferating non-sensory cells. Here we purify from the neonatal mouse cochlea four different non-sensory cell populations by fluorescence-activated cell sorting (FACS). All four populations displayed proliferative potential, but only lesser epithelial ridge and supporting cells robustly gave rise to hair cell marker-positive cells. These results suggest that cochlear supporting cells and cells of the lesser epithelial ridge show robust potential to de-differentiate into prosensory cells that proliferate and undergo differentiation in similar fashion to native prosensory cells of the developing inner ear.

    View details for DOI 10.1038/srep00026

    View details for Web of Science ID 000296046900002

    View details for PubMedID 22355545

    View details for PubMedCentralID PMC3216513

  • Effects of Corticosteroids on Functional Recovery and Neuron Survival After Facial Nerve Injury in Mice ARCHIVES OF FACIAL PLASTIC SURGERY Lieberman, D. M., Jan, T. A., Ahmad, S. O., Most, S. P. 2011; 13 (2): 117-124


    To assess the effects of corticosteroid administration on functional recovery and cell survival in the facial motor nucleus (FMN) following crush injury in adult and juvenile mice and to evaluate the relationship between functional recovery and facial motoneuron survival.A prospective blinded analysis of functional recovery and cell survival in the FMN after crush injury in juvenile and adult mice was carried out. All mice underwent a unilateral facial nerve crush injury and received 7 doses of daily injections. Adults received normal saline or low-dose or high-dose corticosteroid treatment. Juveniles received either normal saline or low-dose corticosteroid treatment. Whisker function was monitored to assess functional recovery. Stereologic analysis was performed to determine neuron and glial survival in the FMN following recovery.Following facial nerve injury, all adult mice recovered fully, while juvenile mice recovered slower and incompletely. This corresponded to a significantly greater neuron loss in the FMN of juveniles compared with adults. Corticosteroid treatment slowed functional recovery in adult mice. This corresponded with significantly greater neuron loss in the FMN in corticosteroid-treated mice. In juvenile mice, corticosteroid treatment showed a trend, which was significant at several time points, toward a more robust functional recovery compared with controls.Corticosteroid treatment slows functional recovery and impairs neuron survival following facial nerve crush injury in adult mice. The degree of motor neuron survival corresponds with functional status. In juvenile mice, crush injury results in overall poor functional recovery and profound cell loss in the FMN. With low-dose corticosteroid treatment, there is a significantly enhanced functional recovery after injury in these mice (P < .05).

    View details for DOI 10.1001/archfacial.2010.98

    View details for PubMedID 21079107

  • Single cell transcriptional profiling reveals heterogeneity of human induced pluripotent stem cells JOURNAL OF CLINICAL INVESTIGATION Narsinh, K. H., Sun, N., Sanchez-Freire, V., Lee, A. S., Almeida, P., Hu, S., Jan, T., Wilson, K. D., Leong, D., Rosenberg, J., Yao, M., Robbins, R. C., Wu, J. C. 2011; 121 (3): 1217-1221


    Human induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs) are promising candidate cell sources for regenerative medicine. However, despite the common ability of hiPSCs and hESCs to differentiate into all 3 germ layers, their functional equivalence at the single cell level remains to be demonstrated. Moreover, single cell heterogeneity amongst stem cell populations may underlie important cell fate decisions. Here, we used single cell analysis to resolve the gene expression profiles of 362 hiPSCs and hESCs for an array of 42 genes that characterize the pluripotent and differentiated states. Comparison between single hESCs and single hiPSCs revealed markedly more heterogeneity in gene expression levels in the hiPSCs, suggesting that hiPSCs occupy an alternate, less stable pluripotent state. hiPSCs also displayed slower growth kinetics and impaired directed differentiation as compared with hESCs. Our results suggest that caution should be exercised before assuming that hiPSCs occupy a pluripotent state equivalent to that of hESCs, particularly when producing differentiated cells for regenerative medicine aims.

    View details for DOI 10.1172/JCI44635

    View details for PubMedID 21317531

  • Isolating LacZ-expressing cells from mouse inner ear tissues using flow cytometry. Journal of visualized experiments : JoVE Jan, T. A., Chai, R., Sayyid, Z. N., Cheng, A. G. 2011: e3432-?


    Isolation of specific cell types allows one to analyze rare cell populations such as stem/progenitor cells. Such an approach to studying inner ear tissues presents a unique challenge because of the paucity of cells of interest and few transgenic reporter mouse models. Here, we describe a protocol using fluorescence-conjugated probes to selectively label LacZ-positive cells from the neonatal cochleae. The most common underlying pathology of sensorineural hearing loss is the irreversible damage and loss of cochlear sensory hair cells, which are required to transduce sound waves to neural impulses. Recent evidence suggests that the murine auditory and vestibular organs harbor stem/progenitor cells that may have regenerative potential. These findings warrant further investigation, including identifying specific cell types with stem/progenitor cell characteristics. The Wnt signaling pathway has been demonstrated to play a critical role in maintaining stem/progenitor cell populations in several organ systems. We have recently identified Wnt-responsive Axin2-expressing cells in the neonatal cochlea, but their function is largely unknown. To better understand the behavior of these Wnt-responsive cells in vitro, we have developed a method of isolating Axin2-expressing cells from cochleae of Axin2-LacZ reporter mice. Using flow cytometry to isolate Axin2-LacZ positive cells from the neonatal cochleae, we could in turn execute a variety of experiments on live cells to interrogate their behavior as stem/progenitor cells. Here, we describe in detail the steps for the microdissection of neonatal cochlea, dissociation of these tissues, labeling of the LacZ-positive cells using a fluorogenic substrate, and cell sorting. Techniques for dissociating cochleae into single cells and isolating cochlear cells via flow cytometry have been described. We have made modifications to these techniques to establish a novel protocol to isolate LacZ-expressing cells from the neonatal cochlea.

    View details for DOI 10.3791/3432

    View details for PubMedID 22217925

    View details for PubMedCentralID PMC3369666

  • Genetic Analysis of Tongue Size and Taste Papillae Number and Size in Recombinant Inbred Strains of Mice CHEMICAL SENSES Reiner, D. J., Jan, T. A., Boughter, J. D., Li, C., Lu, L., Williams, R. W., Waters, R. S. 2008; 33 (8): 693-707


    Quantitative trait loci (QTLs) analysis has been used to examine natural variation of phenotypes in the mouse somatosensory cortex, hippocampus, cerebellum, and amygdala. QTL analysis has also been utilized to map and identify genes underlying anatomical features such as muscle, organ, and body weights. However, this methodology has not been previously applied to identification of anatomical structures related to gustatory phenotypes. In this study, we used QTL analysis to map and characterize genes underlying tongue size, papillae number, and papillae area. In a set of 43 BXD recombinant inbred (RI) mice (n = 111) and 2 parental strains (C57BL/6J and DBA/2J; n = 7), we measured tongue length, width, and weight. In a subset of 23 BXD RI mice and the parental mice, we measured filiform and fungiform papillae number and fungiform papillae area. Using QTL linkage analysis (through WebQTL), we detected 2 significant and noninteracting QTLs influencing tongue length on chromosomes 5 and 7. We also found a significant QTL on chromosome 19 underlying fungiform papillae area and a suggestive QTL on chromosome 2 linked to fungiform papillae number. From these QTLs, we identified a number of candidate genes within the QTL intervals that include SRY-box containing gene, nebulin-related anchoring protein, and actin-binding LIM protein 1. This study is an important first step in identifying genetic factors underlying tongue size, papillae size, and papillae number using QTL analysis.

    View details for DOI 10.1093/chemse/bjn025

    View details for Web of Science ID 000259973600003

    View details for PubMedID 18653645

    View details for PubMedCentralID PMC2565774

  • A functional role for Anopheles gambiae Arrestin1 in olfactory signal transduction JOURNAL OF INSECT PHYSIOLOGY Walker, W. B., Smith, E. M., Jan, T., Zwiebel, L. J. 2008; 54 (4): 680-690


    Insect sensory arrestins act to desensitize visual and olfactory signal transduction pathways, as evidenced by the phenotypic effects of mutations in the genes encoding both Arr1 and Arr2 in Drosophila melanogaster. To assess whether such arrestins play similar roles in other, more medically relevant dipterans, we examined the ability of Anopheles gambiae sensory arrestin homologs AgArr1 and AgArr2 to rescue phenotypes associated with an olfactory deficit observed in D. melanogaster arrestin mutants. Of these, only AgArr1 facilitated significant phenotypic rescue of the corresponding Drosophila arr mutant olfactory phenotype, consistent with the view that functional orthology is shared by these Arr1 homologs. These results represent the first step in the functional characterization of AgArr1, which is highly expressed in olfactory appendages of An. gambiae in which it is likely to play an essential role in olfactory signal transduction. In addition to providing insight into the common elements of the peripheral olfactory system of dipterans, this work validates the importance of AgArr1 as a potential target for novel anti-malaria strategies that focus on olfactory-based behaviors in An. gambiae.

    View details for DOI 10.1016/j.jinsphys.2008.01.007

    View details for Web of Science ID 000255809400005

    View details for PubMedID 18328499

    View details for PubMedCentralID PMC2408752

  • Genetic analysis of posterior medial barrel subfield (PMBSF) size in somatosensory cortex (SI) in recombinant inbred strains of mice BMC NEUROSCIENCE Jan, T. A., Lu, L., Li, C., Williams, R. W., Waters, R. S. 2008; 9


    Quantitative trait locus (QTL) mapping is an important tool for identifying potential candidate genes linked to complex traits. QTL mapping has been used to identify genes associated with cytoarchitecture, cell number, brain size, and brain volume. Previously, QTL mapping was utilized to examine variation of barrel field size in the somatosensory cortex in a limited number of recombinant inbred (RI) strains of mice. In order to further elucidate the underlying natural variation in mouse primary somatosensory cortex, we measured the size of the posterior medial barrel subfield (PMBSF), associated with the representation of the large mystacial vibrissae, in an expanded sample set that included 42 BXD RI strains, two parental strains (C57BL/6J and DBA/2J), and one F1 strain (B6D2F1). Cytochrome oxidase labeling was used to visualize barrels within the PMBSF.We observed a 33% difference between the largest and smallest BXD RI strains with continuous variation in-between. Using QTL linkage analysis from WebQTL, we generated linkage maps of raw total PMBSF and brain weight adjusted total PMBSF areas. After removing the effects of brain weight, we detected a suggestive QTL (likelihood ratio statistic [LRS]: 14.20) on the proximal arm of chromosome 4. Candidate genes under the suggestive QTL peak for PMBSF area were selected based on the number of single nucleotide polymorphisms (SNPs) present and the biological relevance of each gene. Among the candidate genes are Car8 and Rab2. More importantly, mRNA expression profiles obtained using GeneNetwork indicated a strong correlation between total PMBSF area and two genes (Adcy1 and Gap43) known to be important in mouse cortex development. GAP43 has been shown to be critical during neurodevelopment of the somatosensory cortex, while knockout Adcy1 mice have disrupted barrel field patterns.We detected a novel suggestive QTL on chromosome 4 that is linked to PMBSF size. The present study is an important step towards identifying genes underlying the size and possible development of cortical structures.

    View details for DOI 10.1186/1471-2202-9-3

    View details for Web of Science ID 000253536300001

    View details for PubMedID 18179704

    View details for PubMedCentralID PMC2254631

  • Early postnatal alcohol exposure reduced the size of vibrissal barrel field in rat somatosensory cortex (SI) but did not disrupt barrel field organization ALCOHOL Oladehin, A., Margret, C. P., Maier, S. E., Li, C. X., Jan, T. A., Chappell, T. D., Waters, R. S. 2007; 41 (4): 253-261


    Prenatal alcohol exposure (PAE) has been shown to alter the somatosensory cortex in both human and animal studies. In rodents, PAE reduced the size, but not the pattern of the posteromedial barrel subfield (PMBSF) associated with the representation of the whiskers, in newborn, juvenile, and adult rats. However, the PMBSF is not present at birth, but rather first appears in the middle of the first postnatal week during the brain-growth spurt period. These findings raise questions whether early postnatal alcohol exposure might disrupt both barrel field pattern and size, questions that were investigated in the present study. Newborn Sprague-Dawley rats were assigned into alcohol (Alc), nutritional gastric control (GC), and suckle control (SC) groups on postnatal day 4 (P4). Rat pups in Alc and GC were artificially fed with alcohol and maltose-dextrin dissolved in milk, respectively, via an implant gastrostomy tube, from P4 to P9. Pups in the Alc group received alcohol (6.0 g/kg) in milk, while the GC controls received isocaloric equivalent maltose-dextrin dissolved in milk. Pups in the SC group remained with their mothers and breast fed throughout the experimental period. On P10, pups in each group were weighed, sacrificed, and their brains removed and weighed. Cortical hemispheres were separated, weighed, flattened, sectioned tangentially, stained with cytochrome oxidase, and PMBSF measured. The sizes of barrels and the interbarrel septal region within PMBSF, as well as body and brain weights were compared between the three groups. The sizes of PMSBF barrel and septal areas were significantly smaller (P<.01) in Alc group compared to controls, while the PMBSF barrel pattern remained unaltered. Body, whole-brain, forebrain, and hemisphere weights were significantly reduced (P<.01) in Alc pups compared to control groups. GC and SC groups did not differ significantly in all dependent variables, except body weight at P9 and P10 (P<.01). These results suggest that postnatal alcohol exposure, like prenatal exposure, significantly influenced the size of the barrel field, but not barrel field pattern formation, indicating that barrel field pattern formation consolidated prior to P4. These results are important for understanding sensorimotor deficits reported in children suffering from fetal alcohol spectrum disorder (FASD).

    View details for DOI 10.1016/j.alcohol.2007.04.005

    View details for Web of Science ID 000248368000002

    View details for PubMedID 17630086

    View details for PubMedCentralID PMC2435073

  • Prenatal alcohol exposure (PAE) reduces the size of the forepaw representation in forepaw barrel subfield (FBS) cortex in neonatal rats: relationship between periphery and central representation EXPERIMENTAL BRAIN RESEARCH Margret, C. P., Chappell, T. D., Li, C. X., Jan, T. A., Matta, S. G., Elberger, A. J., Waters, R. S. 2006; 172 (3): 387-396


    Prenatal alcohol exposure (PAE) alters limb development that may lead to structural and functional abnormalities of the limb reported in children diagnosed with Fetal Alcohol Spectrum Disorder. To determine whether PAE alters the central representation of the forelimb we used the rodent barrel cortex as our model system where it was possible to visualize and quantitatively measure the size of the forepaw representation in the forepaw barrel subfield (FBS) in first somatosensory cortex. In the present study, we examined the effects of PAE on pattern and size of the forepaw and forepaw representation in FBS in neonatal rats at gestational day 32 that corresponds to postnatal day 9. Pregnant Sprague-Dawley rats were chronically intubated with binge doses of ethanol (6 g/kg) from gestational day 1 through gestational day 20. The offspring of the ethanol treated dams comprised the ethanol (EtOH) group. The effect of PAE on the EtOH group was compared with a nutritional-controlled pairfed (PF) group and a normal chowfed (CF) group. The ventral (glabrous) surface area of the forepaw digits, length of digit 2 through digit 5, and the corresponding glabrous forepaw digit representations in the FBS were measured and compared between treatment groups. In rats exposed to in utero alcohol, the sizes of the overall glabrous forepaw and forepaw digits were significantly reduced in EtOH pups compared to CF and PF pups; overall glabrous forepaw area was 11% smaller than CF controls. Glabrous digit lengths were also smaller in EtOH rats compared to CF controls and significantly smaller in digit 2 through digit 4. The glabrous digit representation in FBS was 18% smaller in the EtOH group when compared to the CF treatment. However, PAE did not produce malformations in the forepaw or alter the pattern of the forepaw representation in FBS; instead, PAE significantly reduced both body and brain weights compared to controls. Unexpectedly, little or no correlation was observed between the size of the glabrous forepaw compared to the size of the glabrous forepaw representation in the FBS for any of the treatment groups. The present findings of PAE-related alterations in sensory periphery and the central cortical representation may underlie deficits in sensorimotor integration reported among children with Fetal Alcohol Spectrum Disorder.

    View details for DOI 10.1007/s00221-005-0339-9

    View details for Web of Science ID 000238151100010

    View details for PubMedID 16424976

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