Jayaraj Rajagopal, MD, MGH Research Scholar Profile
Investigator, Full Prof (M)
Center for Regenerative Medicine, Mass General Research Institute
Professor of Medicine
Harvard Medical School
Bernard and Mildred Kayden MGH Research Institute Chair
Kevin and Polly Maroni MGH Research Scholar 2014-2019
Mass General Research Institute, Massachusetts General Hospital
Associate Member
Broad Institute
HHMI Faculty Scholar
Howard Hughes Medical Institute
Principal Faculty
Harvard Stem Cell Institute
Unit Chief
Stanbury Physician Scientist Pathway
Research Narrative
The lung is a vertebrate invention that allowed the early tetrapods to leave the water and colonize the land. Oxygen is the essential actor in aerobic metabolism and the lung’s cardinal function is to mediate the efficient transfer of oxygen from the atmosphere to the circulatory system. Given the lung’s essential function, diseases of the lung are often life-threatening or incapacitating. Our interest in regeneration is focused on an attempt to understand how cells in a tissue act in concert, as an ensemble, to respond to injury and restore normal tissue form and function.
Recently, we have been interested in topics like plasticity, intercellular signaling circuits operating between different subpopulations of epithelial cells, injury sensing, how tissue form and physiologic function are related, and cellular heterogeneity. But we are open to any and all new avenues that give us insight into how cells act, not as individuals, but as components of a broader cellular tapestry, within the lung, with immune cells, the nervous system, and across organ domains. And we are interested in how all this relates to human lung disease.
The laboratory described the first protocols to direct the differentiation of pluripotent stem cells to airway epithelium. It then made a fundamental contribution to the field of cellular plasticity, discovering that a fully mature functional murine or human cell can durably dedifferentiate into a stem cell. The lab also demonstrated that a stem cell can serve as a niche for its own daughter cells, extending the fundamental concept of the niche first described by Ray Schofield. With the Regev laboratory, the lab discovered pulmonary ionocytes and airway hillocks. Current interests include establishing the functions of a new menagerie of recently discovered lung epithelial cells (ionocytes, tuft cells, neuroendocrine cells, hillocks, and M cells) and their roles in disease. Indeed, the lab recently described the function of airway hillocks in regeneration and as a source of squamous metaplasia. Currently, postdoctoral fellows pursue interests in cell plasticity, regeneration, environmental signal reception, mucosal immunology, infection, and epithelial-nerve interactions.
Bio
Dr. Jayaraj (Jay) Rajagopal is Professor at Harvard Medical School with appointments at the Harvard Stem Cell Institute and the Department of Internal Medicine at Massachusetts General Hospital. He performed his residency in Internal Medicine and Chief Residency at MGH followed by a Pulmonary Critical Care Fellowship. Rajagopal has been a Robertson Investigator of the New York Stem Cell Institute, the Maroni Research Scholar at MGH, an Outstanding Investigator of the International Society for Stem Cell Research, an HHMI Faculty Scholar, and holds the Bernard and Mildred Kayden Endowed Research Institute Chair at MGH. He founded the Stanbury Physician Scientist Pathway and now directs the Stanbury Unit of the MGH Department of Medicine that focuses on the training of young physician-scientists and fostering their careers as independent investigators with their own laboratories.
Education
Dr. Rajagopal received his undergraduate degree summa cum laude in biochemical sciences from Harvard College, with Hoopes and Henderson prizes for his work with Jack Szostak and Jennifer Doudna on ribozyme catalysis. He then received his medical degree (MD) from Harvard Medical School. After finishing his medical training, he joined Doug Melton’s laboratory for postdoctoral studies. While there, he began his work studying the development of the lung and started his own laboratory at MGH in 2010.
Selected References
- Tata PR, Mou H, Pardo-Saganta A, Zhao R, Prabhu M, Law BM, Vinarsky V, Cho JL, Breton S, Sahay A, Medoff BD, Rajagopal J. Dedifferentiation of committed luminal epithelial cells into functional stem cells in vivo. Nature, 2013;503; 218-223.
- Pardo-Saganta A, Law BM, Tata PR, Villoria J, Saez B, Mou H, Zhao R, Rajagopal J. Injury Induces Direct Lineage Segregation of Functionally Distinct Airway Basal Stem/Progenitor Cell Subpopulations. Cell Stem Cell. 2015 Feb 5;16(2):184-197.
- Montoro DT, Haber AL, Biton M, Vinarsky V, Lin B, Birket SE, Yuan F, Chen S, Leung HM, Villoria J, Rogel N, Burgin G, Tsankov AM, Waghray A, Slyper M, Waldman J, Nguyen L, Dionne D, Rozenblatt- Rosen O, Tata PR, Mou H, Shivaraju M, Bihler H, Mense M, Tearney GJ, Rowe SM, Engelhardt JF, Regev A, Rajagopal J. A revised airway epithelial hierarchy includes CFTR- expressing ionocytes. Nature. 2018 Aug 1.560 (7718): 319-324.
- Shivaraju M, Chitta UK, Grange RMH, Jain IH, Capen D, Liao L, Xu J, Ichinose F, Zapol WM, Mootha VK, Rajagopal J. Airway stem cells sense hypoxia and differentiate into protective solitary neuroendocrine cells. Science. 2021 Jan 1;371(6524):52-57.
- Lin B, Shah VS, Chernoff C, Sun J, Shipkovenska GG, Vinarsky V, Waghray A, Xu J, Leduc AD, Hintschich CA, Surve MV, Xu Y, Capen DE, Villoria J, Dou Z, Hariri LP, Rajagopal J. Airway hillocks are injury-resistant reservoirs of unique plastic stem cells. Nature. 2024 May 1. doi: 10.1038/s41586-024-07377-1. Epub ahead of print. PMID: 38693267.