TY - JOUR
T1 - Multi-apical polarity of alveolar stem cells and their dynamics during lung development and regeneration
AU - Konkimalla, Arvind
AU - Konishi, Satoshi
AU - Kobayashi, Yoshihiko
AU - Kadur Lakshminarasimha Murthy, Preetish
AU - Macadlo, Lauren
AU - Mukherjee, Ananya
AU - Elmore, Zachary
AU - Kim, So Jin
AU - Pendergast, Ann Marie
AU - Lee, Patty J.
AU - Asokan, Aravind
AU - Knudsen, Lars
AU - Bravo-Cordero, Jose Javier
AU - Tata, Aleksandra
AU - Tata, Purushothama Rao
N1 - Funding Information:
We thank Brigid Hogan for advice and critical reading of the manuscript and Tata lab members for fruitful discussions. We thank Dr. Stephen Strittmatter (Yale University) for sharing SPRR1A antibody. We thank the Duke University Light Microscopy Core Facility for imaging equipment and consultation, and the Duke Compute Cluster for server space and data storage. We thank the Microscopy and Advanced Bioimaging Core Facility at Mount Sinai. We thank Cagla Eroglu (Duke University) and lab members for providing rat tissue. A.K. is supported by a medical scientist training program fellowship from NHLBI /NIH ( F30HL143911 ). S.K and Y.K. are fellows of the Japan Society for the Promotion of Science Overseas Research. This work was supported by NHLBI/ NIH R01HL151782 grant to A.M.P. This work was supported by an NCI R01 ( CA244780 ) (to J.J.B.C) and the Tisch Cancer Institute NIH Cancer Center grant ( P30 CA196521 ). This work was supported by a Pathways to Independence award from NHLBI/NIH ( R00HL127181 ), ( R01HL146557 , R01HL160939 , and R01HL153375 ), support from the pilot grant support fromNCI/NIH - P30 Cancer Center Support Grant ( P30CA014236 ) to P.R.T. and funds from Regeneration NeXT and Kaganov- MEDx Pulmonary Initiative to P.R.T. at Duke University . This work was partially supported by funds from Whitehead Foundation and P.R.T. is a Whitehead Scholar at Duke University.
Funding Information:
We thank Brigid Hogan for advice and critical reading of the manuscript and Tata lab members for fruitful discussions. We thank Dr. Stephen Strittmatter (Yale University) for sharing SPRR1A antibody. We thank the Duke University Light Microscopy Core Facility for imaging equipment and consultation, and the Duke Compute Cluster for server space and data storage. We thank the Microscopy and Advanced Bioimaging Core Facility at Mount Sinai. We thank Cagla Eroglu (Duke University) and lab members for providing rat tissue. A.K. is supported by a medical scientist training program fellowship from NHLBI/NIH (F30HL143911). S.K and Y.K. are fellows of the Japan Society for the Promotion of Science Overseas Research. This work was supported by NHLBI/NIH R01HL151782 grant to A.M.P. This work was supported by an NCI R01 (CA244780) (to J.J.B.C) and the Tisch Cancer Institute NIH Cancer Center grant (P30 CA196521). This work was supported by a Pathways to Independence award from NHLBI/NIH (R00HL127181), (R01HL146557, R01HL160939, and R01HL153375), support from the pilot grant support fromNCI/NIH - P30 Cancer Center Support Grant (P30CA014236) to P.R.T. and funds from Regeneration NeXT and Kaganov- MEDx Pulmonary Initiative to P.R.T. at Duke University. This work was partially supported by funds from Whitehead Foundation and P.R.T. is a Whitehead Scholar at Duke University. A.K. co-designed, conceived, and performed the experiments, analyzed data and co-wrote the manuscript; S.K. designed and performed experiments and assisted with imaging. P.K.L.M and Y.K. performed single-cell RNA-sequencing and assisted in computational analysis. Z.C.E. A.A. and A.M.P. provided reagents. S.K. and P.J.L. performed smoking exposures. A.M. and J.J.B-C performed live imaging. L.K. performed transmission electron microscopy. A.T. and P.R.T. co-designed, conceived and supervised the work and co-wrote the manuscript. All authors reviewed and edited the manuscript. P.R.T. serves as acting CEO of Iolux Inc. P.R.T. serves as a consultant for Surrozen Inc. Cellarity Inc. and Celldom Inc. on work unrelated to the contents of this manuscript. A.A. is a founder and board director at StrideBio Inc. and Torque Bio Inc. as well as serves as a scientific advisor to Kriya Therapeutics, Atsena Therapeutics, Isolere Bio, Mammoth Biosciences, and Ring Therapeutics on work unrelated to the studies reported in this manuscript. All other authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research.
Publisher Copyright:
© 2022 The Author(s)
PY - 2022/10/21
Y1 - 2022/10/21
N2 - Epithelial cells of diverse tissues are characterized by the presence of a single apical domain. In the lung, electron microscopy studies have suggested that alveolar type-2 epithelial cells (AT2s) en face multiple alveolar sacs. However, apical and basolateral organization of the AT2s and their establishment during development and remodeling after injury repair remain unknown. Thick tissue imaging and electron microscopy revealed that a single AT2 can have multiple apical domains that enface multiple alveoli. AT2s gradually establish multi-apical domains post-natally, and they are maintained throughout life. Lineage tracing, live imaging, and selective cell ablation revealed that AT2s dynamically reorganize multi-apical domains during injury repair. Single-cell transcriptome signatures of residual AT2s revealed changes in cytoskeleton and cell migration. Significantly, cigarette smoke and oncogene activation lead to dysregulation of multi-apical domains. We propose that the multi-apical domains of AT2s enable them to be poised to support the regeneration of a large array of alveolar sacs.
AB - Epithelial cells of diverse tissues are characterized by the presence of a single apical domain. In the lung, electron microscopy studies have suggested that alveolar type-2 epithelial cells (AT2s) en face multiple alveolar sacs. However, apical and basolateral organization of the AT2s and their establishment during development and remodeling after injury repair remain unknown. Thick tissue imaging and electron microscopy revealed that a single AT2 can have multiple apical domains that enface multiple alveoli. AT2s gradually establish multi-apical domains post-natally, and they are maintained throughout life. Lineage tracing, live imaging, and selective cell ablation revealed that AT2s dynamically reorganize multi-apical domains during injury repair. Single-cell transcriptome signatures of residual AT2s revealed changes in cytoskeleton and cell migration. Significantly, cigarette smoke and oncogene activation lead to dysregulation of multi-apical domains. We propose that the multi-apical domains of AT2s enable them to be poised to support the regeneration of a large array of alveolar sacs.
KW - Cell biology
KW - Developmental biology
KW - Stem cells research
UR - http://www.scopus.com/inward/record.url?scp=85138759719&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2022.105114
DO - 10.1016/j.isci.2022.105114
M3 - Article
AN - SCOPUS:85138759719
SN - 2589-0042
VL - 25
JO - iScience
JF - iScience
IS - 10
M1 - 105114
ER -