Purushothama Rao Tata

Overview:

Lung regeneration
Lung stem cells
Cell plasticity
Organoid models
Lung Fibrosis
Single Cell Biology

Positions:

Assistant Professor of Cell Biology

Cell Biology
School of Medicine

Assistant Professor in Medicine

Medicine, Pulmonary, Allergy, and Critical Care Medicine
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Affiliate of the Duke Regeneration Center

Regeneration Next Initiative
School of Medicine

Education:

Ph.D. 2011

University of Ulm (Germany)

Grants:

Mapping Epigenetic Memory of Exposure New To Observe (MEMENTO)

Awarded By
Defense Advanced Research Projects Agency
Role
Co Investigator
Start Date
End Date

Mechanisms of submucosal gland cell mediated airway regeneration

Administered By
Cell Biology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

SOX9 Expression Identifies A Novel Alveolar Stem Cell Population

Administered By
Cell Biology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Systematic identification of AEC2 cell niche components and the conversion of basal stem cells into AEC2 cells ex vivo

Administered By
Basic Science Departments
Awarded By
United Therapeutics Corporation
Role
Principal Investigator
Start Date
End Date

Image-Seq: A high-density microfluidic trap array for single cell transcriptome analysis coupled with image based phenotyping

Administered By
Mechanical Engineering and Materials Science
Awarded By
National Institutes of Health
Role
Co Investigator
Start Date
End Date

Publications:

Defined conditions for long-term expansion of murine and human alveolar epithelial stem cells in three-dimensional cultures.

Alveolar type 2 cells (AT2s) serve as stem cells of the alveoli and restore cell numbers after injury. Here, we describe a detailed protocol for the isolation, purification, and culture of murine and human AT2s. We have developed chemically defined and stroma-free culture conditions that enable expansion and maintenance of AT2s. The culture conditions are scalable and compatible with high-throughput chemical and genetic screenings and can potentially be used to generate large AT2 numbers for cell-based therapies. For complete details on the use and execution of this protocol, please refer to Katsura et al. (2020).
Authors
Konishi, S; Tata, A; Tata, PR
MLA Citation
Konishi, Satoshi, et al. “Defined conditions for long-term expansion of murine and human alveolar epithelial stem cells in three-dimensional cultures.Star Protoc, vol. 3, no. 2, June 2022, p. 101447. Pubmed, doi:10.1016/j.xpro.2022.101447.
URI
https://scholars.duke.edu/individual/pub1523772
PMID
35712012
Source
pubmed
Published In
Star Protocols
Volume
3
Published Date
Start Page
101447
DOI
10.1016/j.xpro.2022.101447

Identification of distinct non-myogenic skeletal-muscle-resident mesenchymal cell populations.

Mesenchymal progenitors of the lateral plate mesoderm give rise to various cell fates within limbs, including a heterogeneous group of muscle-resident mesenchymal cells. Often described as fibro-adipogenic progenitors, these cells are key players in muscle development, disease, and regeneration. To further define this cell population(s), we perform lineage/reporter analysis, flow cytometry, single-cell RNA sequencing, immunofluorescent staining, and differentiation assays on normal and injured murine muscles. Here we identify six distinct Pdgfra+ non-myogenic muscle-resident mesenchymal cell populations that fit within a bipartite differentiation trajectory from a common progenitor. One branch of the trajectory gives rise to two populations of immune-responsive mesenchymal cells with strong adipogenic potential and the capability to respond to acute and chronic muscle injury, whereas the alternative branch contains two cell populations with limited adipogenic capacity and inherent mineralizing capabilities; one of the populations displays a unique neuromuscular junction association and an ability to respond to nerve injury.
Authors
Leinroth, AP; Mirando, AJ; Rouse, D; Kobayahsi, Y; Tata, PR; Rueckert, HE; Liao, Y; Long, JT; Chakkalakal, JV; Hilton, MJ
MLA Citation
Leinroth, Abigail P., et al. “Identification of distinct non-myogenic skeletal-muscle-resident mesenchymal cell populations.Cell Rep, vol. 39, no. 6, May 2022, p. 110785. Pubmed, doi:10.1016/j.celrep.2022.110785.
URI
https://scholars.duke.edu/individual/pub1520200
PMID
35545045
Source
pubmed
Published In
Cell Reports
Volume
39
Published Date
Start Page
110785
DOI
10.1016/j.celrep.2022.110785

GAA Deficiency Disrupts Distal Airway Cells in Pompe Disease

Pompe disease is an autosomal recessive glycogen storage disease caused by mutations in alpha-glucosidase (GAA) - an enzyme responsible of hydrolyzing lysosomal glycogen. GAA deficiency results in systemic lysosomal glycogen accumulation and cellular disruption. Skeletal muscle, motor neuron pathology and airway smooth muscle cells are known to contribute to respiratory insufficiency in Pompe disease, but the role of distal airway cells including alveolar type 1 and type 2 cells (AT1 and AT2, respectively) has not been evaluated. AT1 cells depend on lysosomes for cellular homeostasis to maintain a thin barrier for gas exchange whereas AT2 cells depend on lysosomal structures for surfactant production. Using an established mouse model of Pompe disease, the Gaa-/- mouse, we compared lung histology using Periodic acid-Schiff staining, quantification of immunohistochemistry staining and electron microscopy, and pulmonary mechanics using forced oscillometry FlexiVent system, between Gaa-/- and age-matched wild-type (WT) mice. We also perfomed single cell-RNA seq (scRNA-seq) on the distal airways of Gaa-/- mice. Lysosomal glycogen accumulation and engorged lamellar bodies were observed in the AT2 cells in Gaa-/- but not WT mice. Furthermore, AT2 positive surfactant protein-C (SPC) staining and lysosomal positive lysosomal associated membrane protein 1 (LAMP1) staining is more evident with increased colocalization of LAMP1 with the type 2 cell marker after quantification of each marker in Gaa-/- airway cells. The Gaa-/- mice exhibited a significant decrease in total and central airway resistance (Rrs and Rn, respectively), as well as a significant increase in lung compliance (Crs) versus WT mice. Moreover, in the dimensionless and volume-independent shape constant k that describes the curvature of the upper portion of the deflation limb of the Pressure-Volume curves, a statistically significant change was observed in Gaa-/- mice. This indicates a change in the intrinsic elastic properties of the respiratory system in Pompe disease. Finally, a robust transcriptomic dysregulation in AT1 and AT2 cells was detected scRNA-seq in Gaa-/- mice relative to WT mice. We conclude that GAA enzyme deficiency leads to glycogen accumulation in the distal airway stem cells that may contribute to respiratory impairments in Pompe disease. Our findings will inform the clinical care of patients with Pompe disease and will provide essential information for the development of novel therapies in Pompe disease that will address this airway pathology.
Authors
El Haddad, L; Lai, E; Murthy, P; Tata, PR; ElMallah, MK
MLA Citation
El Haddad, L., et al. “GAA Deficiency Disrupts Distal Airway Cells in Pompe Disease.” Faseb Journal : Official Publication of the Federation of American Societies for Experimental Biology, vol. 36, May 2022. Scopus, doi:10.1096/fasebj.2022.36.S1.L7829.
URI
https://scholars.duke.edu/individual/pub1522137
Source
scopus
Published In
Faseb Journal : Official Publication of the Federation of American Societies for Experimental Biology
Volume
36
Published Date
DOI
10.1096/fasebj.2022.36.S1.L7829

Human distal lung maps and lineage hierarchies reveal a bipotent progenitor.

Mapping the spatial distribution and molecular identity of constituent cells is essential for understanding tissue dynamics in health and disease. We lack a comprehensive map of human distal airways, including the terminal and respiratory bronchioles (TRBs), which are implicated in respiratory diseases1-4. Here, using spatial transcriptomics and single-cell profiling of microdissected distal airways, we identify molecularly distinct TRB cell types that have not-to our knowledge-been previously characterized. These include airway-associated LGR5+ fibroblasts and TRB-specific alveolar type-0 (AT0) cells and TRB secretory cells (TRB-SCs). Connectome maps and organoid-based co-cultures reveal that LGR5+ fibroblasts form a signalling hub in the airway niche. AT0 cells and TRB-SCs are conserved in primates and emerge dynamically during human lung development. Using a non-human primate model of lung injury, together with human organoids and tissue specimens, we show that alveolar type-2 cells in regenerating lungs transiently acquire an AT0 state from which they can differentiate into either alveolar type-1 cells or TRB-SCs. This differentiation programme is distinct from that identified in the mouse lung5-7. Our study also reveals mechanisms that drive the differentiation of the bipotent AT0 cell state into normal or pathological states. In sum, our findings revise human lung cell maps and lineage trajectories, and implicate an epithelial transitional state in primate lung regeneration and disease.
Authors
Kadur Lakshminarasimha Murthy, P; Sontake, V; Tata, A; Kobayashi, Y; Macadlo, L; Okuda, K; Conchola, AS; Nakano, S; Gregory, S; Miller, LA; Spence, JR; Engelhardt, JF; Boucher, RC; Rock, JR; Randell, SH; Tata, PR
MLA Citation
Kadur Lakshminarasimha Murthy, Preetish, et al. “Human distal lung maps and lineage hierarchies reveal a bipotent progenitor.Nature, vol. 604, no. 7904, Apr. 2022, pp. 111–19. Pubmed, doi:10.1038/s41586-022-04541-3.
URI
https://scholars.duke.edu/individual/pub1515768
PMID
35355018
Source
pubmed
Published In
Nature
Volume
604
Published Date
Start Page
111
End Page
119
DOI
10.1038/s41586-022-04541-3

Epigenetic basis of oncogenic-Kras-mediated epithelial-cellular proliferation and plasticity.

Oncogenic Kras induces a hyper-proliferative state that permits cells to progress to neoplasms in diverse epithelial tissues. Depending on the cell of origin, this also involves lineage transformation. Although a multitude of downstream factors have been implicated in these processes, the precise chronology of molecular events controlling them remains elusive. Using mouse models, primary human tissues, and cell lines, we show that, in Kras-mutant alveolar type II cells (AEC2), FOSL1-based AP-1 factor guides the mSWI/SNF complex to increase chromatin accessibility at genomic loci controlling the expression of genes necessary for neoplastic transformation. We identified two orthogonal processes in Kras-mutant distal airway club cells. The first promoted their transdifferentiation into an AEC2-like state through NKX2.1, and the second controlled oncogenic transformation through the AP-1 complex. Our results suggest that neoplasms retain an epigenetic memory of their cell of origin through cell-type-specific transcription factors. Our analysis showed that a cross-tissue-conserved AP-1-dependent chromatin remodeling program regulates carcinogenesis.
Authors
Kadur Lakshminarasimha Murthy, P; Xi, R; Arguijo, D; Everitt, JI; Kocak, DD; Kobayashi, Y; Bozec, A; Vicent, S; Ding, S; Crawford, GE; Hsu, D; Tata, PR; Reddy, T; Shen, X
MLA Citation
Kadur Lakshminarasimha Murthy, Preetish, et al. “Epigenetic basis of oncogenic-Kras-mediated epithelial-cellular proliferation and plasticity.Dev Cell, vol. 57, no. 3, Feb. 2022, pp. 310-328.e9. Pubmed, doi:10.1016/j.devcel.2022.01.006.
URI
https://scholars.duke.edu/individual/pub1509211
PMID
35134344
Source
pubmed
Published In
Dev Cell
Volume
57
Published Date
Start Page
310
End Page
328.e9
DOI
10.1016/j.devcel.2022.01.006

Research Areas:

Organoids
Pulmonary Fibrosis
Regeneration