Dr. Tushar Desai specializes in the treatment of general pulmonary and Interstitial Lung Diseases like Idiopathic Pulmonary Fibrosis (IPF). He has practiced pulmonary medicine since 2002.
Dr. Desai has a special interest in understanding the development and progression of diseases like IPF, Chronic Obstructive Pulmonary Disease (COPD), and lung adenocarcinoma, as well as in understanding how native lung stem cells function to repair the lung gas exchange surface after injury.
- Pulmonary Disease
- Interstitial Lung Diseases
Honors & Awards
Genome Editing to Correct Cystic Fibrosis Mutations in Airway Stem Cells, California Institute of Regenerative Medicine (CIRM) (2017-2019)
Woods Family Endowed Faculty Scholar, Stanford Child Health Research Institute (2016-2021)
In Situ Identification and Mapping of Alveolar Stem Cells at Single Cell Resolution in Human Lungs, NIH/NHLBI (2016-2017)
A Genetic Dissection of Lung Adenoma Initiation and Progression, American Lung Association, Lung Cancer Discovery Award (2015-2017)
Selective Aging of the Lungs: Using Conditional Klotho Deletion to Identify the Basis for Emphysema, Glenn Center for the Biology of Aging Seed Grant 2014 (2015-2017)
Single Cell Profiling and in vivo Cellular Interrogation of Alveolar Stem Cells, NIH/NHLBI (2015-2016)
In Situ Transcriptome Profiling in Histological Sections, Stanford Bio-X Interdisciplinary Initiatives Program 2014 (2014-2016)
Interrogation of Individual Cells to Identify Progenitor Cells and Their Niches (U01), NIH/NHLBI (2014-2016)
ITI Faculty Seed Grant 2014, Stanford Institute for Immunity, Transplantation, and Infection (2014-2015)
Development and Maintenance of the Alveolar Type 1 Cell (K08), NIH/NHLBI (2008-2013)
Fellowship in Pulmonary Research, Parker B. Francis Foundation (2006-2009)
Retinoic Acid in Early Lung Morphogenesis, GlaxoSmithKline Pulmonary Fellowship Award (2002-2003)
Robert Dawson Evans Fellow Excellence in Teaching Award, Boston University School of Medicine, Department of Internal Medicine (2000)
House Officer Research Award, University of Michigan Hospitals, Department of Internal Medicine (1998)
Worth F. Bloom M25 Prize, Tufts University School of Medicine (1995)
Boards, Advisory Committees, Professional Organizations
Member, Scientific Advisory Committee, American Thoracic Society (ATS) (2015 - Present)
Medical Education:Tufts University (1995) MA
Internship:University of Michigan Medical Center (1996) MI
Residency:University of Michigan Medical Center (1998) MI
Board Certification: Pulmonary Disease, American Board of Internal Medicine (2001)
Fellowship:Boston University School of Medicine (2002) MA
BA, Amherst College, Psychology (1991)
MD, MPH, Tufts University School of Medicine, Medicine, Public Health (1995)
Tushar Desai, Pehr Harbury, Daniel Riordan. "United States Patent 62/475,090 Molecular profiling using proximity ligation- in situ hybridization", Leland Stanford Junior University, Mar 22, 2017
Current Research and Scholarly Interests
We attempt to deeply characterize the normal biology of the lung, in vivo and at single cell resolution, using powerful and precise genetic and genomic tools. We then apply our fundamental understanding of lung biology to investigate which specific processes have gone awry in particular lung diseases, using a combination of experimental models and analysis of primary human disease samples. Our belief is that dissecting the specific mechanisms of disease pathogenesis will enable the rational design of highly targeted therapies that have the potential to halt disease without conferring significant off-target toxicities.
- Advanced Cell Biology
BIO 214, BIOC 224, MCP 221 (Win)
Independent Studies (6)
- Directed Reading in Medicine
MED 299 (Aut, Win, Spr, Sum)
- Early Clinical Experience in Medicine
MED 280 (Aut, Win, Spr, Sum)
- Graduate Research
MED 399 (Aut, Win, Spr, Sum)
- Graduate Research
STEMREM 399 (Aut, Win, Spr)
- Medical Scholars Research
MED 370 (Aut, Win, Spr, Sum)
- Undergraduate Research
MED 199 (Aut, Win, Spr, Sum)
- Directed Reading in Medicine
Graduate and Fellowship Programs
Pulmonary & Critical Care Medicine (Fellowship Program)
Automated cell type classification in intact tissues by single-cell molecular profiling.
A major challenge in biology is identifying distinct cell classes and mapping their interactions in vivo. Tissue-dissociative technologies enable deep single cell molecular profiling but do not provide spatial information. We developed a proximity ligation- in situ hybridization technology (PLISH) with exceptional signal strength, specificity, and sensitivity in tissue. Multiplexed data sets can be acquired using barcoded probes and rapid label-image-erase cycles, with automated calculation of single cell profiles, enabling clustering and anatomical re-mapping of cells. We apply PLISH to expression profile ~2,900 cells in intact mouse lung, which identifies and localizes known cell types, including rare ones. Unsupervised classification of the cells indicates differential expression of 'housekeeping' genes between cell types, and re-mapping of two sub-classes of Club cells highlights their segregated spatial domains in terminal airways. By enabling single cell profiling of various RNA species in situ, PLISH can impact many areas of basic and medical research.
View details for DOI 10.7554/eLife.30510
View details for PubMedID 29319504
- Early Identification of Bronchopulmonary Dysplasia Using Novel Biomarkers by Proteomic Screening. American journal of respiratory and critical care medicine 2017
Trinucleotide repeat containing 6c (TNRC6c) is essential for microvascular maturation during distal airspace sacculation in the developing lung.
2017; 430 (1): 214–23
GW182 (also known asTNRC6) family members are critically involved in the final effector phase of miRNA-mediated mRNA repression. The three mammalian paralogs, TNRC6a, b and c, are thought to be redundant based on Argonaute (Ago) binding, tethering assays, and RNAi silencing of individual members in cell lines. To test this idea, we generated TNRC6a, b and c knockout mice. TNRC6a mutants die at mid-gestation, while b- and c- deleted mice are born at a Mendelian ratio. However, the majority of TNRC6b and all TNRC6c mutants die within 24h after birth, the latter with respiratory failure. Necropsy of TNRC6c mutants revealed normal-appearing airways that give rise to abnormally thick-walled distal gas exchange sacs. Immunohistological analysis of mutant lungs demonstrated a normal distribution of bronchiolar and alveolar cells, indicating that loss of TNRC6c did not abrogate epithelial cell differentiation. The cellular kinetics and relative proportions of endothelial, epithelial, and mesenchymal cells were also not altered. However, the underlying capillary network was simplified and endothelial cells had failed to become tightly apposed to the surface epithelium in TNRC6c mutants, presumably causing the observed respiratory failure. TGFβ family mutant mice exhibit a similar lung phenotype of thick-walled air sacs and neonatal lethality, and qRT-PCR confirmed dynamic downregulation of TGFβ1 and TGFβR2 in TNRC6c mutant lungs during sacculation. VEGFR, but not VEGF-A ligand, was also lower, likely reflecting the overall reduced capillary density in TNRC6c mutants. Together, these results demonstrate that GW182 paralogs are not functionally redundant in vivo. Surprisingly, despite regulating a general cellular process, TNRC6c is selectively required only in the distal lung and not until late in gestation for proper expression of the TGFβ family genes that drive sacculation. These results imply a complex and indirect mode of regulation of sacculation by TNRC6c, mediated in part by dynamic transcriptional repression of an inhibitor of TGFβ family gene expression.
View details for DOI 10.1016/j.ydbio.2017.07.018
View details for PubMedID 28811219
Attenuated PDGF signaling drives alveolar and microvascular defects in neonatal chronic lung disease.
EMBO molecular medicine
Neonatal chronic lung disease (nCLD) affects a significant number of neonates receiving mechanical ventilation with oxygen-rich gas (MV-O2). Regardless, the primary molecular driver of the disease remains elusive. We discover significant enrichment for SNPs in the PDGF-Rα gene in preterms with nCLD and directly test the effect of PDGF-Rα haploinsufficiency on the development of nCLD using a preclinical mouse model of MV-O2 In the context of MV-O2, attenuated PDGF signaling independently contributes to defective septation and endothelial cell apoptosis stemming from a PDGF-Rα-dependent reduction in lung VEGF-A. TGF-β contributes to the PDGF-Rα-dependent decrease in myofibroblast function. Remarkably, endotracheal treatment with exogenous PDGF-A rescues both the lung defects in haploinsufficient mice undergoing MV-O2 Overall, our results establish attenuated PDGF signaling as an important driver of nCLD pathology with provision of PDGF-A as a protective strategy for newborns undergoing MV-O2.
View details for DOI 10.15252/emmm.201607308
View details for PubMedID 28923828
- Hedgehog-driven myogenic tumors recapitulate skeletal muscle cellular heterogeneity EXPERIMENTAL CELL RESEARCH 2016; 340 (1): 43-52
Keeping it together: Pulmonary alveoli are maintained by a hierarchy of cellular programs.
2015; 37 (9): 1028-1037
The application of in vivo genetic lineage tracing has advanced our understanding of cellular mechanisms for tissue renewal in organs with slow turnover, like the lung. These studies have identified an adult stem cell with very different properties than classically understood ones that maintain continuously cycling tissues such as the intestine. A portrait has emerged of an ensemble of cellular programs that replenish the cells that line the gas exchange (alveolar) surface, enabling a response tailored to the extent of cell loss. A capacity for differentiated cells to undergo direct lineage transitions allows for local restoration of proper cell balance at sites of injury. We present these recent findings as a paradigm for how a relatively quiescent tissue compartment can maintain homeostasis throughout a lifetime punctuated by injuries ranging from mild to life-threatening, and discuss how dysfunction or insufficiency of alveolar repair programs produce serious health consequences like cancer and fibrosis.
View details for DOI 10.1002/bies.201500031
View details for PubMedID 26201286
Cellular mechanisms of alveolar pathology in childhood interstitial lung diseases: current insights from mouse genetics
CURRENT OPINION IN PEDIATRICS
2015; 27 (3): 341-347
Childhood interstitial lung diseases (ILDs) are a diverse class of disorders affecting the alveolar gas exchange region that lack specific treatments and are usually fatal. Here, we integrate recent insights into alveolar cell biology with histopathology from well characterized mutations of surfactant-associated genes. We take a reductionist approach by parsing discrete histological features and correlating each to perturbation of a particular function of the alveolar epithelial type II (AT2) cell, the central driver of disease, to generate a working model for the cellular mechanisms of disease pathogenesis.The application of genetically modified mice and single cell genomics has yielded new insights into lung biology, including the identification of a bipotent alveolar progenitor in development, mapping of adult AT2 stem cells in vivo, and demonstration that latent cooperative interactions with fibroblasts can be pathologically activated by targeted injury of the AT2 cell.As we learn more about individual and cooperative roles for alveolar cells in health, we can dissect how perturbations of specific cellular functions contribute to disease in childhood ILDs. We hope our updated model centered around the AT2 cell as the initiator of disease provides a cellular framework that researchers can build upon and revise as they identify the specific molecular signals within and between alveolar cells that mediate the diverse pathologic features, so that targeted pharmacologic and cell-based treatments for patients can ultimately be engineered.
View details for DOI 10.1097/MOP.0000000000000227
View details for Web of Science ID 000354214800013
View details for PubMedID 25888154
Reconstructing lineage hierarchies of the distal lung epithelium using single-cell RNA-seq.
2014; 509 (7500): 371-375
The mammalian lung is a highly branched network in which the distal regions of the bronchial tree transform during development into a densely packed honeycomb of alveolar air sacs that mediate gas exchange. Although this transformation has been studied by marker expression analysis and fate-mapping, the mechanisms that control the progression of lung progenitors along distinct lineages into mature alveolar cell types are still incompletely known, in part because of the limited number of lineage markers and the effects of ensemble averaging in conventional transcriptome analysis experiments on cell populations. Here we show that single-cell transcriptome analysis circumvents these problems and enables direct measurement of the various cell types and hierarchies in the developing lung. We used microfluidic single-cell RNA sequencing (RNA-seq) on 198 individual cells at four different stages encompassing alveolar differentiation to measure the transcriptional states which define the developmental and cellular hierarchy of the distal mouse lung epithelium. We empirically classified cells into distinct groups by using an unbiased genome-wide approach that did not require a priori knowledge of the underlying cell types or the previous purification of cell populations. The results confirmed the basic outlines of the classical model of epithelial cell-type diversity in the distal lung and led to the discovery of many previously unknown cell-type markers, including transcriptional regulators that discriminate between the different populations. We reconstructed the molecular steps during maturation of bipotential progenitors along both alveolar lineages and elucidated the full life cycle of the alveolar type 2 cell lineage. This single-cell genomics approach is applicable to any developing or mature tissue to robustly delineate molecularly distinct cell types, define progenitors and lineage hierarchies, and identify lineage-specific regulatory factors.
View details for DOI 10.1038/nature13173
View details for PubMedID 24739965
- Alveolar progenitor and stem cells in lung development, renewal and cancer. Nature 2014; 507 (7491): 190-194
- Stem cells: Differentiated cells in a back-up role. Nature 2013; 503 (7475): 204-205
Smooth muscle protein 22 alpha-mediated patchy deletion of Bmpr1a impairs cardiac contractility but protects against pulmonary vascular remodeling
2008; 102 (3): 380-388
Vascular expression of bone morphogenetic type IA receptor (Bmpr1a) is reduced in lungs of patients with pulmonary arterial hypertension, but the significance of this observation is poorly understood. To elucidate the role of Bmpr1a in the vascular pathology of pulmonary arterial hypertension and associated right ventricular (RV) dysfunction, we deleted Bmpr1a in vascular smooth muscle cells and in cardiac myocytes in mice using the SM22alpha;TRE-Cre/LoxP;R26R system. The LacZ distribution reflected patchy deletion of Bmpr1a in the lung vessels, aorta, and heart of SM22alpha;TRE-Cre;R26R;Bmpr1a(flox/+) and flox/flox mutants. This reduction in BMPR-IA expression was confirmed by Western immunoblot and immunohistochemistry in the flox/flox group. This did not affect pulmonary vasoreactivity to acute hypoxia (10% O2) or the increase in RV systolic pressure and RV hypertrophy following 3 weeks in chronic hypoxia. However, both SM22alpha;TRE-Cre;R26R;Bmpr1a(flox/+) and flox/flox mutant mice had fewer muscularized distal pulmonary arteries and attenuated loss of peripheral pulmonary arteries compared with age-matched control littermates in hypoxia. When Bmpr1a expression was reduced by short interference RNA in cultured pulmonary arterial smooth muscle cells, serum-induced proliferation was attenuated explaining decreased hypoxia-mediated muscularization of distal vessels. When Bmpr1a was reduced in cultured microvascular pericytes by short interference RNA, resistance to apoptosis was observed and this could account for protection against hypoxia-mediated vessel loss. The similar elevation in RV systolic pressure and RV hypertrophy, despite the attenuated remodeling with chronic hypoxia in the flox/flox mutants versus controls, was not a function of elevated left ventricular end diastolic pressure but was associated with increased periadventitial deposition of elastin and collagen, potentially influencing vascular stiffness.
View details for DOI 10.1161/CIRCRESAHA.107.161059
View details for Web of Science ID 000253194600018
View details for PubMedID 18079409
- In vitro and in vivo gene therapy vector evolution via multispecies interbreeding and retargeting of adeno-associated viruses J Virol 2008; 82 (12): 5887-5911
Inhibition of Tgf beta signaling by endogenous retinoic acid is essential for primary lung bud induction
2007; 134 (16): 2969-2979
Disruption of retinoic acid (RA) signaling during early development results in severe respiratory tract abnormalities, including lung agenesis. Previous studies suggest that this might result from failure to selectively induce fibroblast growth factor 10 (Fgf10) in the prospective lung region of the foregut. Little is known about the RA-dependent pathways present in the foregut that may be crucial for lung formation. By performing global gene expression analysis of RA-deficient foreguts from a genetic [retinaldehyde dehydrogenase 2 (Raldh2)-null] and a pharmacological (BMS493-treated) mouse model, we found upregulation of a large number of Tgfbeta targets. Increased Smad2 phosphorylation further suggested that Tgfbeta signaling was hyperactive in these foreguts when lung agenesis was observed. RA rescue of the lung phenotype was associated with low levels of Smad2 phosphorylation and downregulation of Tgfbeta targets in Raldh2-null foreguts. Interestingly, the lung defect that resulted from RA-deficiency could be reproduced in RA-sufficient foreguts by hyperactivating Tgfbeta signaling with exogenous TGF beta 1. Preventing activation of endogenous Tgfbeta signaling with a pan-specific TGFbeta-blocking antibody allowed bud formation and gene expression in the lung field of both Raldh2-null and BMS493-treated foreguts. Our data support a novel mechanism of RA-Tgfbeta-Fgf10 interactions in the developing foregut, in which endogenous RA controls Tgfbeta activity in the prospective lung field to allow local expression of Fgf10 and induction of lung buds.
View details for DOI 10.1242/dev.006221
View details for Web of Science ID 000248385000009
View details for PubMedID 17634193
Distinct roles for retinoic acid receptors alpha and beta in early lung morphogenesis
2006; 291 (1): 12-24
Retinoic acid (RA) signaling is required for normal development of multiple organs. However, little is known about how RA influences the initial stages of lung development. Here, we used a combination of genetic, pharmacological and explant culture approaches to address this issue, and to investigate how signaling by different RA receptors (RAR) mediates the RA effects. We analyzed initiation of lung development in retinaldehyde dehydrogenase-2 (Raldh2) null mice, a model in which RA signaling is absent from the foregut from its earliest developmental stages. We provide evidence that RA is dispensable for specification of lung cell fate in the endoderm. By using synthetic retinoids to selectively activate RAR alpha or beta signaling in this model, we demonstrate novel and unique functions of these receptors in the early lung. We show that activation of RAR beta, but not alpha, induces expression of the fibroblast growth factor Fgf10 and bud morphogenesis in the lung field. Similar analysis of wild type foregut shows that endogenous RAR alpha activity is required to maintain overall RA signaling, and to refine the RAR beta effects in the lung field. Our data support the idea that balanced activation of RAR alpha and beta is critical for proper lung bud initiation and endodermal differentiation.
View details for DOI 10.1016/j.ydbio.2005.10.045
View details for Web of Science ID 000236128300002
View details for PubMedID 16427040
Retinoic acid selectively regulates Fgf10 expression and maintains cell identity in the prospective lung field of the developing foregut
2004; 273 (2): 402-415
Although respiratory tract defects that result from disruption of retinoic acid (RA) signaling have been widely reported, the mechanism by which endogenous RA regulates early lung morphogenesis is unknown. Here, we provide novel evidence that a major role for RA is to selectively maintain mesodermal proliferation and induce fibroblast growth factor 10 (Fgf10) expression in the foregut region where the lung forms. By using a pan-RAR antagonist (BMS493) in foregut explant cultures, we show that bud initiation is selectively blocked in the prospective respiratory region by failure to induce Fgf10 in the corresponding mesoderm. The RA regulation of Fgf10 expression occurs only in this region, within a defined developmental window, and is not seen in other foregut derivatives such as thyroid and pancreas where Fgf10 is also required for normal development. Furthermore, we show that RA activity is essential in the lung field to maintain lung cell identity in the endoderm; RAR antagonism disrupts expression of thyroid transcription factor 1 (Ttf1), an early marker of the respiratory region in the endoderm, and surfactant protein C (Sp-C) mRNAs. Our observations in mouse foregut cultures are corroborated by data from an in vivo model of vitamin A deficiency in rats. Our study supports RA as an essential regulator of gene expression and cellular activities during primary bud formation.
View details for DOI 10.1016/j.ydbio.2004.04.039
View details for Web of Science ID 000223681000018
View details for PubMedID 15328022
- COPD: Clinical Manifestations, Diagnosis, and Treatment Baum's Textbook of Pulmonary Diseases (Eds: James D. Crapo, Jeffrey Glassroth, Joel Karlinsky, and Talmadge E. King Jr.) 2004; 7th ed
Growth factors in lung development and disease: friends or foe?
2002; 3: 2-?
Growth factors mediate tissue interactions and regulate a variety of cellular functions that are critical for normal lung development and homeostasis. Besides their involvement in lung pattern formation, growth and cell differentiation during organogenesis, these factors have been also implicated in modulating injury-repair responses of the adult lung. Altered expression of growth factors, such as transforming growth factor beta1, vascular endothelial growth factor and epidermal growth factor, and/or their receptors, has been found in a number of pathological lung conditions. In this paper, we discuss the dual role of these molecules in mediating beneficial feedback responses or responses that can further damage lung integrity; we shall also discuss the basis for their prospective use as therapeutic agents.
View details for PubMedID 11806837
View details for PubMedCentralID PMC64813
Participation of urokinase-type plasminogen activator receptor in the clearance of fibrin from the lung
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
1999; 277 (3): L573-L579
In vitro studies have demonstrated that the binding of urokinase-type plasminogen activator (uPA) to its cell surface receptor (uPAR) greatly accelerates plasminogen activation. However, the role of uPAR in clearing abnormal fibrin deposits from the lung is uncertain. Knowing that uPA binding to uPAR is species specific, we used adenoviral vectors to transfer human or murine uPA genes into human or mouse epithelial cells in vitro and to mouse lungs in vivo. By measuring degradation of fluorescein-labeled fibrin, we found that uPA lysed fibrin matrices more efficiently when expressed in cells of the same species. A monoclonal antibody that blocks the binding of human uPA to human uPAR suppressed fibrin degradation by human cells expressing human uPA but not murine uPA. Importantly, 3 days after intratracheal delivery of the vectors, mice receiving murine uPA transgenes degraded fibrin matrices formed within their air spaces more efficiently than animals transduced with human uPA genes. These results show that uPA bound to uPAR increases the efficiency of fibrinolysis on epithelial cell surfaces in a biologically relevant fashion.
View details for Web of Science ID 000082425100017
View details for PubMedID 10484465