About our work
Dysfunctions in the RPE are thought to be the initiating events leading to degenerative eye diseases. Therefore, a better understanding of the disease initiating pathways in RPE will provide a basis for therapeutic interventions. In collaboration with the NEI clinic, we are obtaining skin biopsies from patients with clinically diagnosed degenerative eye diseases. These biopsies are being used to derive iPS cells. RPE cells differentiated from such iPS cells are used to study events that have led to disease initiation and progression.
In collaboration with National Center for Advancing Translational Sciences (NCATS), we have combined the patient-specific iPSC approach with high throughput screening assays performed in 384-well plates to identify novel compounds that could act as potential therapeutic agents. In collaboration with new NIH Center for Regenerative Medicine, we are developing iPSC-derived RPE tissue for cell-based therapy. We have modified the existing stem cell to RPE differentiation protocols to make them more complaint with current Good Manufacturing Practices (cGMP-work).
Our work uses the most cutting edge technologies in the field and aims to translate these technologies to a clinical use.
Our research mission
The goal of the Ocular and Stem Cell Translational Research Unit is to perform translational research on degenerative eye diseases using induced pluripotent stem (iPS) cell technology. We are using this technology to develop in vitro disease models to study patient-specific disease processes, to set up high through drug screens, and to develop cell-based therapy for retinal degenerative disease.
Our translational goals are focused on retinal pigment epithelium (RPE), a monolayer of highly polarized cells located in the back of the eye, whose apical processes inter-digitate with photoreceptor outer segments. RPE performs several functions that are absolutely critical for the health and integrity of photoreceptors. Some of these functions include regulating nutrient and metabolite flow, maintaining ionic homeostasis in the sub-retinal space, regenerating visual pigment, and phagocytizing shed photoreceptor outer segments.
Jobs, fellowships, and internships
Nasonkin, I., Merbs, S., Lazo, K., Oliver, V., Brooks, M., Patel, K., Enke, R., Nellissery, J., Jamrich, M., Le, Y., Bharti, K., Rachel, R., Fariss, R., Zack, D., Rodriguez-Boulan, E., Swaroop, A. (2013) Conditional knockdown of DNA methyltransferase-1 (Dnmt1) reveals a key role of retinal pigment epithelium in mammalian photoreceptor differentiation. Development 140: 1330-1341.
Ou, J., Bharti, K., Nodari, A., Bertuzzi, S., and Arnheiter, H. (2013) Vax1/2 genes counteract Mitf-induced respecification of the retinal pigment epithelium. PLoSOne 8 (3): e59247.
Yan, Y., Shin, S., Jha, B, Liu, Q., Shen, J., Zhan, M., Davis, J., Bharti, K., Zeng, X., Rao, M., Malik, N., and Vemuri, M. (2013) Efficient and rapid derivation of primitive neural stem cells and generation of brain subtype neurons from human pluripotent stem cells. Stem Cells Translational Medicine 2 (11): 862-870.
Forni, P., Bharti, K., Flannery, E., Shimogori, T., and Wray, S. (2013) The indirect role of FGF8 in defining neurogenic niches of the olfactory/GnRH systems. J. Neuroscience 33 (50): 19620-19634.
Greer, Y.E., Westlake, C.J., Gao, B., Bharti, K., Kim, K., Shiba, Y., Sokol, S., Yang, Y., and Rubin, J. (2014) Casein kinase 1 delta is a mediator of ciliogenesis. Mol. Biol. Cell 25 (10): 1629-1640.
Raviv, S., Bharti, K., Rencus-Lazar, S., Cohen-Tayar, Y., Schyr, R., Evantal, N., Meshorer, Zilberberg, A.E., Reubinoff, B., Grebe, R., Rosin-Arbesfeld, R., Lauderdale, J., Lutty, G., Arnheiter, H., Ashery-Padan, R., (2014) PAX6 regulates melanogenesis in the retinal pigment epithelium through feed-forward regulatory interactions with MITF. PLoS Genetics 10 (5): e1004360.
Ferrer, M., Corneo, B., Davis, J., Wan, Q., Miyagishima, K.J., King, R., Maminishkis, A., Marugan, J., Sharma, R., Shure, M., Temple, S., Miller, S., and Bharti, K. (2014) A multiplex high-throughput gene expression assay to simultaneously detect disease and functional markers in induced pluripotent stem cell-derived retinal pigment epithelium. Stem Cells Translational Medicine 3:1-12.
Hotaling, N.A., Bharti, K., Kriel, H., and Simon, C.G. (2015) Validated open source nanofiber diameter measurement tool. Biomaterials 61: 327-338.
Maruotti, J., Sripathi, S.R., Bharti, K., Fuller, J., Wahlin, K., Ranganathan, V., Sluch, V., Berlinicke, C., Davis, J., Kim, C., Zhao, L., Wan, J., Qian, J., Corneo, B., Temple, S., Dubey, R., Olenyuk, B., Bhutto, I., Lutty, G., and Zack, D.J., (2015) Small molecule directed efficient generation of retinal pigment epithelium from human pluripotent stem cells. PNAS 112 (35): 10950-10955.
Hotaling, N.A., Bharti, K., Kriel, H., and Simon, C.G. (2015) Dataset for the validation and use of DiameterJ an open source nanofiber diameter measurement tool. Data In Brief 5: 13-22.
Blenkinsop, T.A., Saini, J.S., Maminishkis, A., Bharti, K., Wan, Q., Banzon, T., Lotfi, M., Davis, J., Singh, D., Rizzolo, L.J., Miller, S., Temple, S., and Stern, J.H. (2015) Human Adult Retinal Pigment Epithelial Stem Cell-derived RPE Monolayers Exhibit Key Physiological Characteristics of Native Tissue. IOVS 56 (12): 7085-7099.
Miyagishimaa, K., Wan, Q., Corneo, Q., Sharma, R., Lotfi, M., Boles, N., Hua, F., Maminishkis, A., Zhang, C., Blenkinsop, T., Khristov, V., Jha, B., Memon, O., D’Souza, S., Temple, S., Miller, S., Bharti, K. (2016) In Pursuit of Authenticity: iPS Cell-derived RPE for Clinical Applications. Stem Cells Translational Medicine 5 (11) 1562-1574.
Hotaling, N.A., Jeon, J., Wade, M.B., Luong, D., Palmer, X-L., Bharti, K., and Simon, C.G. (2016) Training to Improve Precision and Accuracy in the Measurement of Fiber Morphology. PLoSOne 11 (12): e01676664.
George, A., Zand, D.J., Hufnagel, R.B., Sharma, R., Sergeev, Y., Legare, J.M., Rice, G.M., Schwoerer, J.A., Rius, M., Gamm, D.M., Bharti, K.*, and Brooks, B.P. (2016) COMMAD: a Novel Syndrome Caused by Biallelic Mutation of the MITF Gene. Am. J. Hum. Genet. 99 (6): 1388-1394. *Co-senior author.
Keir, L.S., Firth, R., Aponik, L., Feitelberg, D., Sakimoto, S., Aguilar, E., Welsh, G.I., Richards, A., Usui, Y., Satchell, S.C., Kuzmuk, V., Coward, R.J., Goult, J., Bull, K.R., Sharma, R., Bharti, K., Westenskow, P.D., Michael, I.P., Saleem, M.A., and Friedlander, M., (2016) VEGF regulates local inhibitory complement proteins in the eye and kidney. J. Clin. Investigations (epubl. Dec ).
Sharma, R., Khristov, V., Rising, A., Jha,B.S., Dejene, R., Hotaling, N., Li, Y., Stoddard,J., Stankewicz,C., Wan, Q., Zhang, C., Campos, M.M., Miyagishima, K.J., McGaughey, D., Villasmil, R., Mattapallil, M., Stanzel, B., Qian, H., Wong, W., Chase, L., Charles, S., McGill, T., Miller, S., Maminishkis, A., Amaral, J., and Bharti, K., (2019) Clinical-grade Stem Cell–derived Retinal Pigment Epithelium Patch Rescues Retinal Degeneration in Rodents and Pigs. Science Translational Medicine 11, eaat5580 (2019) 1-13.
Reviews and chapters
Bharti, K., Nguyen, M., Skuntz, S., Bertuzzi, S., and Arnheiter, H. (2006) The other pigment cell—the pigment epithelium of the eye. Pig. Cell Res. 19: 380-394.
Bharti, K.*, Miller, S.S., and Arnheiter, H. (2011) The new paradigm: Retinal pigment epithelium cells generated from embryonic stem cells or induced pluripotent stem cells. Pig. Cell Melanoma Res. 24: 21-34. *Corresponding author
Bharti, K.*, Rao, M., Hull, S.C., Stroncek, D., Brooks, B.P., Feigal, E., van Meurs, J.C., Huang, C.A., and Miller, S. (2014) Developing cellular therapies for retinal degenerative diseases. IOVS 55 (2): 1191-1202. *Corresponding author
Jha, S.B. and Bharti, K. (2015) Regenerating retinal pigment epithelial cells to cure blindness: a road towards personalized artificial tissue. Current Stem Cell Reports. 1 (2): 79-91.
Song, M.J. and Bharti, K. (2015) Looking into the future: using induced pluripotent stem cells to build two and three dimensional ocular tissue for cell therapy and disease modeling. Brain Research. 1638 (Part A): 2-14.
Hotaling, N.A., Khristov, V., Wan, Q., Sharma, R., Jha, B.S., Lotfi, M., Maminishkis, A., Simon, C.G., and Bharti, K. (2016) Nanofiber Scaffold Based Tissue Engineered Retinal Pigment Epithelium to Treat Degenerative Eye Diseases. Journal of Ocular Pharmacology and Therapeutics. 32 (5): 272-285.
Miyagishima, K.J., Wan, Q., Miller, S.S., and Bharti, K. (2017) A Basis for Comparison: Sensitive Authentication of Stem Cell Derived RPE Using Physiological Responses of Intact RPE Monolayers. Stem Cell & Translational Investigation. 4: e1497.