Multi-apical polarity of alveolar stem cells and their dynamics during lung development and regeneration

Konkimalla, Arvind; Konishi, Satoshi; Kobayashi, Yoshihiko; Murthy, Preetish Kadur Lakshminarasimha; Macadlo, Lauren; Mukherjee, Ananya; Elmore, Zachary C.; Kim, Sojin; Pendergast, Ann Marie; Lee, Patricia; Asokan, Aravind; Knudsen, Lars; Bravo-Cordero, Jose Javier; Tata, Aleksandra; Tata, Purushothama Rao

doi:10.1016/j.isci.2022.105114

Cited by 9 publications

(6 citation statements)

References 74 publications

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“…Quantifying the spatiotemporal dynamics of individual alveolar stem cells during injury response requires high-resolution live imaging of large numbers of AT2 cells over an extended period. Previous attempts to image AT2 cells in situ in their native environment have been limited by short durations (<1d) and low-throughput 8,9 . To overcome these barriers, we sought to create a platform that would allow for high-resolution imaging of alveolar tissue over a period of days following injury in a controlled and highly reproducible manner.…”

Section: Resultsmentioning

confidence: 99%

“…Following injury, AT2 cells are responsible for generating new cells in order to repopulate damaged alveoli 14,17,[33][34][35] . Recent studies have revealed that one of the earliest steps of AT2 cell differentiation is their commitment to a Krt8 + transitional cell state [36][37][38][39][40][41][42][43] and that that this transitional cell state is enriched for the expression of motility genes 38,44 . To better understand the relationship between the onset of stem cell motility and cell fate commitment we analyzed publicly available single-cell sequencing data of AT2 cells after injury (GSE141259) 38 using Manifold Interpolating Optimal-Transport Flows for Trajectory Inference (MIOFLOW).…”

Section: Inhibition Of Motility Prevents Alveolar Stem Cell Fate Comm...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…In part, this has been due to the technical challenges associated with capturing and quantifying individual stem cell behaviors in situ in real time, particularly in organs that are difficult to image such as the lung. 8,9 Some adult stem/progenitor cells become motile following injury [1][2][3][4][5][6] and this has been linked to their capacity to repair [1][2][3] . For example, intravital imaging of mammalian wound repair has shown how stem cells in the hair follicle undergo directed migration to sites of injury in the epidermis 7 .…”

Section: Introductionmentioning

confidence: 99%

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Spatiotemporal coordination of stem cell behavior following alveolar injury

Chioccioli

Magruder

McDonough

et al. 2022

Preprint

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Tissue repair requires a highly coordinated cellular response to ensure the correct balance of replacement cells to lost cells. In the lung, alveolar type 2 (AT2) cells act as stem cells and can replace both themselves and alveolar type 1 cells (AT1); however, the complex orchestration of AT2 stem cell activity following lung injury is poorly understood owing to the inability to track individual stem cells and their dynamic behavior over time. Here, we apply live time lapse imaging to ex vivo mouse precision cut lung slice (PCLS) culture and in vivo mouse lung to track individual GFP-labeled AT2 cells for 72h following intra-tracheal administration of bleomycin. We observe highly dynamic movement of AT2 cells, including migration within and between alveoli, as well as the emergence of at least three distinct morphokinetic AT2 cell states. Small molecule-based inhibition of Rho-associated protein kinase (ROCK) pathway significantly reduced motility of AT2 stem cells following injury and reduced expression of Krt8, a known marker of intermediate progenitor cells. Together, our results uncover motility of alveolar stem cells as a new injury response mechanism in the lung and uncover properties of stem cell motility at high cellular resolution.

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Section: Resultsmentioning

confidence: 99%

Section: Inhibition Of Motility Prevents Alveolar Stem Cell Fate Comm...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Spatiotemporal coordination of stem cell behavior following alveolar injury

Chioccioli

Magruder

McDonough

et al. 2022

Preprint

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“…Thereby, AE2 cells are in direct contact with more than one alveolus ( Figure 2 ). This configuration strategically positions one AE2 cell to be able to supply surfactant to and regenerate the alveolar epithelium in multiple alveoli via its multipolar apical domains ( Konkimalla et al, 2022 ).…”

Section: An Overview Of the Functional Design Of The Lungmentioning

confidence: 99%

Acinar micromechanics in health and lung injury: what we have learned from quantitative morphology

et al. 2023

Self Cite

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Within the pulmonary acini ventilation and blood perfusion are brought together on a huge surface area separated by a very thin blood-gas barrier of tissue components to allow efficient gas exchange. During ventilation pulmonary acini are cyclically subjected to deformations which become manifest in changes of the dimensions of both alveolar and ductal airspaces as well as the interalveolar septa, composed of a dense capillary network and the delicate tissue layer forming the blood-gas barrier. These ventilation-related changes are referred to as micromechanics. In lung diseases, abnormalities in acinar micromechanics can be linked with injurious stresses and strains acting on the blood-gas barrier. The mechanisms by which interalveolar septa and the blood-gas barrier adapt to an increase in alveolar volume have been suggested to include unfolding, stretching, or changes in shape other than stretching and unfolding. Folding results in the formation of pleats in which alveolar epithelium is not exposed to air and parts of the blood-gas barrier are folded on each other. The opening of a collapsed alveolus (recruitment) can be considered as an extreme variant of septal wall unfolding. Alveolar recruitment can be detected with imaging techniques which achieve light microscopic resolution. Unfolding of pleats and stretching of the blood-gas barrier, however, require electron microscopic resolution to identify the basement membrane. While stretching results in an increase of the area of the basement membrane, unfolding of pleats and shape changes do not. Real time visualization of these processes, however, is currently not possible. In this review we provide an overview of septal wall micromechanics with focus on unfolding/folding as well as stretching. At the same time we provide a state-of-the-art design-based stereology methodology to quantify microarchitecture of alveoli and interalveolar septa based on different imaging techniques and design-based stereology.

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Cancer treatments as paradoxical catalysts of tumor awakening in the lung

Nicolas,

Kosmider,

Cukierman

et al. 2024

Cancer Metastasis Rev

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Much of the fatality of tumors is linked to the growth of metastases, which can emerge months to years after apparently successful treatment of primary tumors. Metastases arise from disseminated tumor cells (DTCs), which disperse through the body in a dormant state to seed distant sites. While some DTCs lodge in pre-metastatic niches (PMNs) and rapidly develop into metastases, other DTCs settle in distinct microenvironments that maintain them in a dormant state. Subsequent awakening, induced by changes in the microenvironment of the DTC, causes outgrowth of metastases. Hence, there has been extensive investigation of the factors causing survival and subsequent awakening of DTCs, with the goal of disrupting these processes to decrease cancer lethality. We here provide a detailed overview of recent developments in understanding of the factors controlling dormancy and awakening in the lung, a common site of metastasis for many solid tumors. These factors include dynamic interactions between DTCs and diverse epithelial, mesenchymal, and immune cell populations resident in the lung. Paradoxically, among key triggers for metastatic outgrowth, lung tissue remodeling arising from damage induced by the treatment of primary tumors play a significant role. In addition, growing evidence emphasizes roles for inflammation and aging in opposing the factors that maintain dormancy. Finally, we discuss strategies being developed or employed to reduce the risk of metastatic recurrence.

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Multi-apical polarity of alveolar stem cells and their dynamics during lung development and regeneration

Cited by 9 publications

References 74 publications

Spatiotemporal coordination of stem cell behavior following alveolar injury

Spatiotemporal coordination of stem cell behavior following alveolar injury

Acinar micromechanics in health and lung injury: what we have learned from quantitative morphology

Cancer treatments as paradoxical catalysts of tumor awakening in the lung

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