Aravind Sivakumar

Jawaharlal Institute of Post Graduate Medical Education and Research

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David B. Frank

University of Pennsylvania

MinQi Lu

Children's Hospital of Philadelphia

Natasza A. Kurpios

Cornell University

Edward E. Morrisey

University of Pennsylvania

Jarod A. Zepp

Children's Hospital of Philadelphia

Sowmya Jayachandran

University of Pennsylvania

Apoorva Babu

University of Pennsylvania

Jeremy Katzen

University of Pennsylvania

J. Pankin

Children's Hospital of Philadelphia

Michael P. Morley

University of Pennsylvania

Cooperative Institutions

University of Pennsylvania

Children's Hospital of Philadelphia

Philadelphia University

Penn Center for AIDS Research

California University of Pennsylvania

Hospital of the University of Pennsylvania

Cornell University

Cardiovascular Institute of the South

Lung Institute

Pulmonary and Allergy Associates

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Re-Initiation of Developmental Paradigms for Regeneration After Neonatal Lung Injury

David B. Frank Sowmya Jayachandran Aravind Sivakumar MinQi Lu Kwaku Quansah

10.1164/ajrccm-conference.2020.201.1_meetingabstracts.a7679

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The Left-Right Pitx2 Pathway Drives Organ-Specific Arterial and Lymphatic Development in the Intestine

Developmental Cell (2014)

Aparna Mahadevan Ian Welsh Aravind Sivakumar David W. Gludish Abigail R. Shilvock

Arteriogenesis

Lymphangiogenesis

PITX2

10.1016/j.devcel.2014.11.002

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Citations (101)

STAT3–BDNF–TrkB signalling promotes alveolar epithelial regeneration after lung injury

Nature Cell Biology (2020)

Andrew J. Paris Katharina E. Hayer Joseph H. Oved Daphne C. Avgousti Sushila A. Toulmin

10.1038/s41556-020-0569-x

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Citations (96)

mTORC1 activation in lung mesenchyme drives sex- and age-dependent pulmonary structure and function decline

Nature Communications (2020)

Kseniya Obraztsova Maria C. Basil Ryan W. Rue Aravind Sivakumar Susan M. Lin

Abstract Lymphangioleiomyomatosis (LAM) is a rare fatal cystic lung disease due to bi-allelic inactivating mutations in tuberous sclerosis complex (TSC1/TSC2) genes coding for suppressors of the mechanistic target of rapamycin complex 1 (mTORC1). The origin of LAM cells is still unknown. Here, we profile a LAM lung compared to an age- and sex-matched healthy control lung as a hypothesis-generating approach to identify cell subtypes that are specific to LAM. Our single-cell RNA sequencing (scRNA-seq) analysis reveals novel mesenchymal and transitional alveolar epithelial states unique to LAM lung. This analysis identifies a mesenchymal cell hub coordinating the LAM disease phenotype. Mesenchymal-restricted deletion of Tsc2 in the mouse lung produces a mTORC1-driven pulmonary phenotype, with a progressive disruption of alveolar structure, a decline in pulmonary function, increase of rapamycin-sensitive expression of WNT ligands, and profound female-specific changes in mesenchymal and epithelial lung cell gene expression. Genetic inactivation of WNT signaling reverses age-dependent changes of mTORC1-driven lung phenotype, but WNT activation alone in lung mesenchyme is not sufficient for the development of mouse LAM-like phenotype. The alterations in gene expression are driven by distinctive crosstalk between mesenchymal and epithelial subsets of cells observed in mesenchymal Tsc2 -deficient lungs. This study identifies sex- and age-specific gene changes in the mTORC1-activated lung mesenchyme and establishes the importance of the WNT signaling pathway in the mTORC1-driven lung phenotype.

Mesenchyme

TSC2

Lymphangioleiomyomatosis

10.1038/s41467-020-18979-4

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Citations (44)

Spatiotemporal Lineage Mapping to Define Molecular Crossroads of Heart Versus Lung Mesodermal Fate

David B. Frank Kwaku Quansah Sowmya Jayachandran MinQi Lu J. Pankin

Lineage (genetic)

Fate mapping

Cell fate determination

10.1164/ajrccm-conference.2020.201.1_meetingabstracts.a5985

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Paradigms That Define Lung Epithelial Progenitor Cell Fate in Development and Regeneration

Current Stem Cell Reports (2019)

Aravind Sivakumar David B. Frank

Progenitor

Cell fate determination

Fate mapping

10.1007/s40778-019-00166-x

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Citations (7)

A CXCL12 morphogen gradient uncovers lung endothelial heterogeneity and promotes distal vascular growth

bioRxiv (Cold Spring Harbor Laboratory) (2022)

Prashant Chandrasekaran Nicholas M. Negretti Aravind Sivakumar Maureen Peers de Nieuwburgh Joanna Wang

Abstract In adults, there is a growing amount of data uncovering the cellular diversity of the pulmonary circulation and mechanisms governing vascular repair after injury, however, molecular and cellular mechanisms contributing to the morphogenesis and growth of the pulmonary vasculature during embryonic development are less clear. Importantly, deficits in vascular development lead to a large number of lung diseases in children, indicating a need to uncover fetal programs that promote pulmonary vascular growth. To address this, we used a transgenic mouse reporter for expression of Cxcl12 , an arterial hallmark gene, and performed single-cell RNA sequencing on isolated Cxcl12 -DsRed+ endothelium to assess cellular heterogeneity within pulmonary endothelium. Combining cell annotation, gene ontology analysis, and spatial transcriptomics allowed us to segregate the developing artery into spatially and functionally distinct novel subpopulations. In addition, expression of Cxcl12 suggests a morphogen gradient from arteries to capillaries, suggesting directed cell migration for pulmonary vascular development. Disruption of this gradient led to abnormal branching and pulmonary vascular hypoplasia. These data provide evidence for arterial endothelial functional heterogeneity and reveal conserved signaling mechanisms essential for pulmonary vascular development.

Morphogen

10.1101/2022.04.30.490096

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Early lineage specification defines alveolar epithelial ontogeny in the murine lung

Proceedings of the National Academy of Sciences (2019)

David B. Frank Ian J. Penkala Jarod A. Zepp Aravind Sivakumar Ricardo Linares-Saldana

During the stepwise specification and differentiation of tissue-specific multipotent progenitors, lineage-specific transcriptional networks are activated or repressed to orchestrate cell specification. The gas-exchange niche in the lung contains two major epithelial cell types, alveolar type 1 (AT1) and AT2 cells, and the timing of lineage specification of these cells is critical for the correct formation of this niche and postnatal survival. Integrating cell-specific lineage tracing studies, spatially specific mRNA transcript and protein expression, and single-cell RNA-sequencing analysis, we demonstrate that specification of alveolar epithelial cell fate begins concomitantly with the proximal–distal specification of epithelial progenitors and branching morphogenesis earlier than previously appreciated. By using a newly developed dual-lineage tracing system, we show that bipotent alveolar cells that give rise to AT1 and AT2 cells are a minor contributor to the alveolar epithelial population. Furthermore, single-cell assessment of the transcriptome identifies specified AT1 and AT2 progenitors rather than bipotent cells during sacculation. These data reveal a paradigm of organ formation whereby lineage specification occurs during the nascent stages of development coincident with broad tissue-patterning processes, including axial patterning of the endoderm and branching morphogenesis.

Lineage (genetic)

Progenitor

Cell type

10.1073/pnas.1813952116

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Citations (134)

Midgut Laterality Is Driven by Hyaluronan on the Right

Developmental Cell (2018)

Aravind Sivakumar Aparna Mahadevan Mark Lauer Ricky J. Narvaez Siddesh Ramesh

10.1016/j.devcel.2018.08.002

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Citations (55)

Visualizing and manipulating the production and accumulation of hyaluronan for functional assessment in chicken embryos

STAR Protocols (2023)

Bhargav D. Sanketi Aravind Sivakumar Natasza A. Kurpios

Hyaluronan (HA) accumulates in the extracellular matrix to regulate organ morphogenesis. The spatiotemporal dynamics of its production and function are poorly understood due to its instability. Here, we present a protocol using the embryonic chicken intestine as a binary in vivo system for HA visualization and manipulation. We describe steps for pharmacological manipulation and in ovo electroporation to target HA production and accumulation. We then detail HA-binding protein assay to detect HA accumulation and quantification of tissue morphology changes. For complete details on the use and execution of this protocol, please refer to Sivakumar et al. (2018)

In ovo

10.1016/j.xpro.2023.102200

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Citations (1)