- Email: [email protected]
May the (Mechanical) Force Be with AT2
McHeyzer-Williams, L.J., Milpied, P.J., Okitsu, S.L., and McHeyzer-Williams, M.G. (2015). Classswitched memory B cells remodel BCRs within secondary germinal centers. Nat. Immunol. 16, 296–305. Mesin, L., Schiepers, A., Ersching, J., Barbulescu, A., Cavazzoni, C.B., Angelini, A., Okada, T., Kurosaki, T., and Victora, G.D. (2020). Restricted Clonality and Limited Germinal Center Reentry Characterize Memory B Cell Reactivation by Boosting. Cell 180, this issue, 92–106.
Tessema, S.K., Nakajima, R., Jasinskas, A., Monk, S.L., Lekieffre, L., Lin, E., Kiniboro, B., Proietti, C., Siba, P., Felgner, P.L., et al. (2019). Protective Immunity against Severe Malaria in Children Is Associated with a Limited Repertoire of Antibodies to Conserved PfEMP1 Variants. Cell Host Microbe 26, 579–590.e5. Victora, G.D., and Wilson, P.C. (2015). Germinal center selection and the antibody response to influenza. Cell 163, 545–548. Wu, X., Zhang, Z., Schramm, C.A., Joyce, M.G., Kwon, Y.D., Zhou, T., Sheng, Z., Zhang, B.,
O’Dell, S., McKee, K., et al.; NISC Comparative Sequencing Program (2015). Maturation and Diversity of the VRC01-Antibody Lineage over 15 Years of Chronic HIV-1 Infection. Cell 161, 470–485. Zuccarino-Catania, G.V., Sadanand, S., Weisel, F.J., Tomayko, M.M., Meng, H., Kleinstein, S.H., Good-Jacobson, K.L., and Shlomchik, M.J. (2014). CD80 and PD-L2 define functionally distinct memory B cell subsets that are independent of antibody isotype. Nat. Immunol. 15, 631–637.
May the (Mechanical) Force Be with AT2 Julio Sainz de Aja1,2,3 and Carla F. Kim1,2,3,* 1Stem Cell Program, Division of Hematology/Oncology and Division of Respiratory Disease, Boston Children’s Hospital, Boston, MA 02115, USA 2Department of Genetics, Harvard Medical School, Boston, MA 02115, USA 3Harvard Stem Cell Institute, Cambridge, MA 02138, USA *Correspondence: [email protected] https://doi.org/10.1016/j.cell.2019.12.020
Idiopathic pulmonary fibrosis is a fatal disease involving destruction of the lung alveolar structure. In this issue of Cell, Wu et al. (2020) show that impaired alveolar (AT2) stem cells produce mechanical tension that leads to spatially regulated fibrosis, initiating a new chapter in understanding what underlies the periphery to center progression of this lung disease. A long time ago in a lung far, far away . so goes the limited understanding of how idiopathic pulmonary fibrosis (IPF) develops; very little is understood of the early stages or the progression of this deadly disease. Fibrosis involves an over-proliferation of fibroblasts and the accumulation of extracellular matrix. In the lung, the most common type of fibrosis is idiopathic pulmonary fibrosis. Clinical studies have documented that this disease starts in the periphery and progresses toward the center of the lung (Figure 1) (Plantier et al., 2011), yet why this occurs is unknown. The concept of mechanical tension as a driver of IPF has been previously contemplated but never formally proven in a fibrotic progression context (Zhang et al., 2015). It is known that IPF affects alveolar type II (AT2) cells, the stem cells of the lung’s alveolar units. However, the mechanisms by which AT2 cells contribute to IPF path-
ogenesis are still unknown. In this issue of Cell, Wu et al. (2020) now link the mechanical tension caused by lung fibrosis to impaired alveolar stem cells. Elevated mechanical tension caused by defective alveolar stem cells generates an activation loop of TGFß signaling that is more substantial in the lung periphery and eventually extends toward the central part of the lung, explaining a long-standing question about IPF. The findings bridge an important new link between stem cell defects and fibrosis and while doing so provide new ways to model the disease. For the first time, their paper shows that a differentiation defect in lung alveolar stem cells (AT2 cells) stimulates fibrosis progression. Previously, Tang and colleagues connected Cdc42, a member of the RhoGTPase family, with alveolar regeneration—a connection that implies stem cell involvement (Liu et al., 2016). Wu
20 Cell 180, January 9, 2020 ª 2019 Elsevier Inc.
et al. (2020) show that in mice with Cdc42-null AT2 cells, there is no new generation of alveolar type I cells, the pneumocytes that perform gas exchange. Thus, Cdc42-null AT2 cells have a differentiation defect. As a consequence, mice lacking Cdc42 in AT2 cells after injury or with aging develop a progressive fibrosis. Because the disease in these mice does not resolve and more closely resembles the spatial-temporal aspects of human disease progression, this could be a better way to model fibrosis than the widely used bleomyocin injury. Interestingly, Cdc42 could also provide a connection to another cellular process linked to IPF. Previous studies have shown accelerated epithelial senescence plays a role in IPF pathogenesis (Minagawa et al., 2011), and Cdc42 is involved in senescence (Wang et al., 2007). Indeed, the concept
Figure 1. Defective Alveolar Stem Cells and Associated Mechanical Tension Lead to Spatially Specific Fibrotic Progression The figure depicts a wild-type lung lobe (left) and a lung lobe with alveolar stem cell (AT2)-specific Cdc42 knockout (KO) (right). The Cdc42 KO AT2 cells are unable to differentiate to AT1 cells, the pneumocytes that perform gas exchange. In combination with partial lung pneumonectomy, this stem cell defect leads to an increase in the mechanical tension. The gradient of colors (right lobe) portrays the fibrotic progression (arrows) that proceeds from the periphery toward the center of the lung in a spatial-specific fashion as a result of the mechanical changes. This is the physiological way in which idiopathic pulmunary fibrosis progresses and therefore might be a better model of the disease.
that senescent cells in the lung periphery and possibly even in airways are at the root of IPF has now taken hold of the IPF field; senolytics are a favorite strategy for alleviating IPF in drug-discovery avenues. A very recent pre-print from Stripp and colleagues addresses this by inducing senescence in AT2 cells by knocking out Sin3a (Yao et al., 2019). Remarkably, the mice with Sin3a-knockout AT2 cells also develop fibrosis that progresses peripherally to centrally. With the emergence of these new mouse models of fibrosis, the tools needed to bring even more insight into the cellular defects involved in this disease are likely to follow.
Much like Wu et al. (2020), a number of recent studies have implicated new cell types, or perhaps new cellular states, in PF. Single-cell RNA sequencing has been used for analyzing lung fibrosis in a number of recently published papers and pre-prints (Adams et al., 2019; Habermann et al., 2019; Reyfman et al., 2019). The motivation for these lines of investigation developed out of a necessity in the field to identify the cell of origin in fibrosis and the cell-cell interactions that can modify the behavior of the aberrant fibroblasts, which are the ultimate effectors of the disease. It is interesting that in two of these works, they identify a unique cell type described by Adams et al. (2019)
as ‘‘aberrant basaloids cells.’’ This cell type is believed to come from a transitional AT2 cell population. Now, Wu et al. (2020) identify yet another potential subpopulation of AT2 cells. The question remains whether and how all the specialized AT2 cell populations that have been characterized to date are related to one another and, more importantly, to human disease. In the study from Tang and colleagues, a newly appreciated subset of AT2 cells that could resemble an intermediate state between AT2 and AT1 cells harkens an early phase of disease progression. Although Wu et al. (2020) do not make the claim that these cells initiate IPF, they hold defective AT2 cells responsible for increasing mechanical tension and setting off a cascade of TGFb signaling leading to progression of this deadly disease. So is mechanical tension on the dark side or the light side of lung stem cell biology? Mechanical forces are critical in lung development. The Tang group and many others before have shown that signals from mechanical force are required for alveologenesis in response to induced lung injury. With the new insight that stem cells can cause aberrant tension, the negative aspects of this could present therapeutic opportunities. In this paper, the authors unveil the importance of the relationship among the physical forces, stem cells, and biochemical reactions in the lung to shape a lethal disease for which there is still no cure. Nevertheless, more experiments are needed to support the role of mechanical tension in the spatial progression of the fibrotic disease. For example, are there key mechano-sensors that activate the downstream signaling pathway, and if so, in which cell type do they operate? As a related question, how do defective alveolar stem cells interact with mesenchymal cells and extracellular matrices (ECM)? Can tension be modulated or maintained to a healthy degree to halt progression of fibrosis in patients? Are other IPF models equally dependent on mechanical tension? If so, what are the specific parameters that play a central role: surface tension, susceptibility to stretching, rigidity of the cytoplasm, and/ or stiffening of the niche? How can we use this information to create a more
Cell 180, January 9, 2020 21
meaningful culture model of IPF? Can we recapitulate the features of the defective alveolar stem cells in the dish in order to screen for factors that modulate this activity? Do defective stem cells in other tissues lead to aberrant mechanical forces and contribution to fibrosis in other organs? Unlike the newest Star Wars movie, this work by Wu et al. (2020) is certainly not the last chapter because it opens new ways to understand and possibly treat fibrosis. ACKNOWLEDGMENTS
lung resident cell populations in Idiopathic Pulmonary Fibrosis. bioRxiv. https://doi.org/10.1101/ 759902. Habermann, A.C., Gutierrez, A.J., Bui, L.T., Yahn, S.L., Winters, N.I., Calvi, C.L., Peter, L., Chung, M.-I., Taylor, C.J., Jetter, C., et al. (2019). Singlecell RNA-sequencing reveals profibrotic roles of distinct epithelial and mesenchymal lineages in pulmonary fibrosis. bioRxiv. https://doi.org/10. 1101/753806. Liu, Z., Wu, H., Jiang, K., Wang, Y., Zhang, W., Chu, Q., Li, J., Huang, H., Cai, T., Ji, H., et al. (2016). MAPK-Mediated YAP Activation Controls Mechanical-Tension-Induced Pulmonary Alveolar Regeneration. Cell Rep. 16, 1810–1819.
REFERENCES
Minagawa, S., Araya, J., Numata, T., Nojiri, S., Hara, H., Yumino, Y., Kawaishi, M., Odaka, M., Morikawa, T., Nishimura, S.L., et al. (2011). Accelerated epithelial cell senescence in IPF and the inhibitory role of SIRT6 in TGF-b-induced senescence of human bronchial epithelial cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 300, L391–L401.
Adams, T.S., Schupp, J.C., Poli, S., Ayaub, E.A., Neumark, N., Ahangari, F., Chu, S.G., Raby, B.A., DeIuliis, G., Januszyk, M., et al. (2019). Single Cell RNA-seq reveals ectopic and aberrant
Plantier, L., Crestani, B., Wert, S.E., Dehoux, M., Zweytick, B., Guenther, A., and Whitsett, J.A. (2011). Ectopic respiratory epithelial cell differentiation in bronchiolised distal airspaces in idiopathic pulmonary fibrosis. Thorax 66, 651–657.
We thank members of the Kim lab and the many labs whose work could not be cited because of space limits. C.F.K. is supported in part by National Institutes of Health grants R01 HL132266 and R01 HL125821 and the Celgene IDEAL Consortium.
Reyfman, P.A., Walter, J.M., Joshi, N., Anekalla, K.R., McQuattie-Pimentel, A.C., Chiu, S., Fernandez, R., Akbarpour, M., Chen, C.-I., Ren, Z., et al. (2019). Single-Cell Transcriptomic Analysis of Human Lung Provides Insights into the Pathobiology of Pulmonary Fibrosis. Am. J. Respir. Crit. Care Med. 199, rccm.201712–2410OC. Wang, L., Yang, L., Debidda, M., Witte, D., and Zheng, Y. (2007). Cdc42 GTPase-activating protein deficiency promotes genomic instability and premature aging-like phenotypes. Proc. Natl. Acad. Sci. USA 104, 1248–1253. Wu, H., Yu, Y., Huang, H., Hu, Y., Fu, S., Wang, Z., Shi, M., Zhao, X., Yuan, J., Li, J., et al. (2020). Progressive Pulmonary Fibrosis Is Caused by Elevated Mechanical Tension on Alveolar Stem Cells. Cell 180, this issue, 107–121. Yao, C., Guan, X., Carraro, G., Parimon, T., Liu, X., Huang, G., Soukiasian, H.J., David, G., Weigt, S.S., Belperio, J.A., et al. (2019). Senescence of alveolar stem cells drives progressive pulmonary fibrosis. bioRxiv. https://doi.org/10.1101/820175. Zhang, R., Pan, Y., Fanelli, V., Wu, S., Luo, A.A., Islam, D., Han, B., Mao, P., Ghazarian, M., Zeng, W., et al. (2015). Mechanical Stress and the Induction of Lung Fibrosis via the Midkine Signaling Pathway. Am. J. Respir. Crit. Care Med. 192, 315–323.
Every Breath You Take: New Insights into Plant and Animal Oxygen Sensing Daniel J. Gibbs1,* and Michael J. Holdsworth2,** 1School
of Biosciences, University of Birmingham, Edgbaston, B15 2TT, UK of Biosciences, University of Nottingham, Loughborough, LE12 5RD, UK *Correspondence: [email protected] (D.J.G.), [email protected] (M.J.H.) https://doi.org/10.1016/j.cell.2019.10.043 2School
Responses to hypoxia are regulated by oxygen-dependent degradation of kingdom-specific proteins in animals and plants. Masson et al. (2019) identified and characterized the mammalian counterpart of an oxygen-sensing pathway previously only observed in plants. Alongside other recent findings identifying novel oxygen sensors, this provides new insights into oxygen-sensing origins and mechanisms in eukaryotes. Oxygen is essential to almost all life on earth, being required for respiration and a wide range of cellular biochemistry. Multicellular eukaryotes evolved in response to the oxidation events that increased oxygen levels during Earth history, and mechanisms for directly sensing and responding to oxygen avail-
ability are found broadly across taxa. In metazoan animals and higher plants, transcriptional responses to reduced oxygen (hypoxia) are achieved by oxygen-dependent degradation of transcription factors through analogous but mechanistically distinct post-translational modifications. A recent study published in Science
22 Cell 180, January 9, 2020 ª 2019 Elsevier Inc.
showed that an oxygen-sensing enzyme first described in plants is also present in humans, revealing a conserved mechanism that transduces responses to hypoxia in both kingdoms (Masson et al., 2019). In animals, gene expression in response to hypoxia is coordinated by
Tessema, S.K., Nakajima, R., Jasinskas, A., Monk, S.L., Lekieffre, L., Lin, E., Kiniboro, B., Proietti, C., Siba, P., Felgner, P.L., et al. (2019). Protective Immunity against Severe Malaria in Children Is Associated with a Limited Repertoire of Antibodies to Conserved PfEMP1 Variants. Cell Host Microbe 26, 579–590.e5. Victora, G.D., and Wilson, P.C. (2015). Germinal center selection and the antibody response to influenza. Cell 163, 545–548. Wu, X., Zhang, Z., Schramm, C.A., Joyce, M.G., Kwon, Y.D., Zhou, T., Sheng, Z., Zhang, B.,
O’Dell, S., McKee, K., et al.; NISC Comparative Sequencing Program (2015). Maturation and Diversity of the VRC01-Antibody Lineage over 15 Years of Chronic HIV-1 Infection. Cell 161, 470–485. Zuccarino-Catania, G.V., Sadanand, S., Weisel, F.J., Tomayko, M.M., Meng, H., Kleinstein, S.H., Good-Jacobson, K.L., and Shlomchik, M.J. (2014). CD80 and PD-L2 define functionally distinct memory B cell subsets that are independent of antibody isotype. Nat. Immunol. 15, 631–637.
May the (Mechanical) Force Be with AT2 Julio Sainz de Aja1,2,3 and Carla F. Kim1,2,3,* 1Stem Cell Program, Division of Hematology/Oncology and Division of Respiratory Disease, Boston Children’s Hospital, Boston, MA 02115, USA 2Department of Genetics, Harvard Medical School, Boston, MA 02115, USA 3Harvard Stem Cell Institute, Cambridge, MA 02138, USA *Correspondence: [email protected] https://doi.org/10.1016/j.cell.2019.12.020
Idiopathic pulmonary fibrosis is a fatal disease involving destruction of the lung alveolar structure. In this issue of Cell, Wu et al. (2020) show that impaired alveolar (AT2) stem cells produce mechanical tension that leads to spatially regulated fibrosis, initiating a new chapter in understanding what underlies the periphery to center progression of this lung disease. A long time ago in a lung far, far away . so goes the limited understanding of how idiopathic pulmonary fibrosis (IPF) develops; very little is understood of the early stages or the progression of this deadly disease. Fibrosis involves an over-proliferation of fibroblasts and the accumulation of extracellular matrix. In the lung, the most common type of fibrosis is idiopathic pulmonary fibrosis. Clinical studies have documented that this disease starts in the periphery and progresses toward the center of the lung (Figure 1) (Plantier et al., 2011), yet why this occurs is unknown. The concept of mechanical tension as a driver of IPF has been previously contemplated but never formally proven in a fibrotic progression context (Zhang et al., 2015). It is known that IPF affects alveolar type II (AT2) cells, the stem cells of the lung’s alveolar units. However, the mechanisms by which AT2 cells contribute to IPF path-
ogenesis are still unknown. In this issue of Cell, Wu et al. (2020) now link the mechanical tension caused by lung fibrosis to impaired alveolar stem cells. Elevated mechanical tension caused by defective alveolar stem cells generates an activation loop of TGFß signaling that is more substantial in the lung periphery and eventually extends toward the central part of the lung, explaining a long-standing question about IPF. The findings bridge an important new link between stem cell defects and fibrosis and while doing so provide new ways to model the disease. For the first time, their paper shows that a differentiation defect in lung alveolar stem cells (AT2 cells) stimulates fibrosis progression. Previously, Tang and colleagues connected Cdc42, a member of the RhoGTPase family, with alveolar regeneration—a connection that implies stem cell involvement (Liu et al., 2016). Wu
20 Cell 180, January 9, 2020 ª 2019 Elsevier Inc.
et al. (2020) show that in mice with Cdc42-null AT2 cells, there is no new generation of alveolar type I cells, the pneumocytes that perform gas exchange. Thus, Cdc42-null AT2 cells have a differentiation defect. As a consequence, mice lacking Cdc42 in AT2 cells after injury or with aging develop a progressive fibrosis. Because the disease in these mice does not resolve and more closely resembles the spatial-temporal aspects of human disease progression, this could be a better way to model fibrosis than the widely used bleomyocin injury. Interestingly, Cdc42 could also provide a connection to another cellular process linked to IPF. Previous studies have shown accelerated epithelial senescence plays a role in IPF pathogenesis (Minagawa et al., 2011), and Cdc42 is involved in senescence (Wang et al., 2007). Indeed, the concept
Figure 1. Defective Alveolar Stem Cells and Associated Mechanical Tension Lead to Spatially Specific Fibrotic Progression The figure depicts a wild-type lung lobe (left) and a lung lobe with alveolar stem cell (AT2)-specific Cdc42 knockout (KO) (right). The Cdc42 KO AT2 cells are unable to differentiate to AT1 cells, the pneumocytes that perform gas exchange. In combination with partial lung pneumonectomy, this stem cell defect leads to an increase in the mechanical tension. The gradient of colors (right lobe) portrays the fibrotic progression (arrows) that proceeds from the periphery toward the center of the lung in a spatial-specific fashion as a result of the mechanical changes. This is the physiological way in which idiopathic pulmunary fibrosis progresses and therefore might be a better model of the disease.
that senescent cells in the lung periphery and possibly even in airways are at the root of IPF has now taken hold of the IPF field; senolytics are a favorite strategy for alleviating IPF in drug-discovery avenues. A very recent pre-print from Stripp and colleagues addresses this by inducing senescence in AT2 cells by knocking out Sin3a (Yao et al., 2019). Remarkably, the mice with Sin3a-knockout AT2 cells also develop fibrosis that progresses peripherally to centrally. With the emergence of these new mouse models of fibrosis, the tools needed to bring even more insight into the cellular defects involved in this disease are likely to follow.
Much like Wu et al. (2020), a number of recent studies have implicated new cell types, or perhaps new cellular states, in PF. Single-cell RNA sequencing has been used for analyzing lung fibrosis in a number of recently published papers and pre-prints (Adams et al., 2019; Habermann et al., 2019; Reyfman et al., 2019). The motivation for these lines of investigation developed out of a necessity in the field to identify the cell of origin in fibrosis and the cell-cell interactions that can modify the behavior of the aberrant fibroblasts, which are the ultimate effectors of the disease. It is interesting that in two of these works, they identify a unique cell type described by Adams et al. (2019)
as ‘‘aberrant basaloids cells.’’ This cell type is believed to come from a transitional AT2 cell population. Now, Wu et al. (2020) identify yet another potential subpopulation of AT2 cells. The question remains whether and how all the specialized AT2 cell populations that have been characterized to date are related to one another and, more importantly, to human disease. In the study from Tang and colleagues, a newly appreciated subset of AT2 cells that could resemble an intermediate state between AT2 and AT1 cells harkens an early phase of disease progression. Although Wu et al. (2020) do not make the claim that these cells initiate IPF, they hold defective AT2 cells responsible for increasing mechanical tension and setting off a cascade of TGFb signaling leading to progression of this deadly disease. So is mechanical tension on the dark side or the light side of lung stem cell biology? Mechanical forces are critical in lung development. The Tang group and many others before have shown that signals from mechanical force are required for alveologenesis in response to induced lung injury. With the new insight that stem cells can cause aberrant tension, the negative aspects of this could present therapeutic opportunities. In this paper, the authors unveil the importance of the relationship among the physical forces, stem cells, and biochemical reactions in the lung to shape a lethal disease for which there is still no cure. Nevertheless, more experiments are needed to support the role of mechanical tension in the spatial progression of the fibrotic disease. For example, are there key mechano-sensors that activate the downstream signaling pathway, and if so, in which cell type do they operate? As a related question, how do defective alveolar stem cells interact with mesenchymal cells and extracellular matrices (ECM)? Can tension be modulated or maintained to a healthy degree to halt progression of fibrosis in patients? Are other IPF models equally dependent on mechanical tension? If so, what are the specific parameters that play a central role: surface tension, susceptibility to stretching, rigidity of the cytoplasm, and/ or stiffening of the niche? How can we use this information to create a more
Cell 180, January 9, 2020 21
meaningful culture model of IPF? Can we recapitulate the features of the defective alveolar stem cells in the dish in order to screen for factors that modulate this activity? Do defective stem cells in other tissues lead to aberrant mechanical forces and contribution to fibrosis in other organs? Unlike the newest Star Wars movie, this work by Wu et al. (2020) is certainly not the last chapter because it opens new ways to understand and possibly treat fibrosis. ACKNOWLEDGMENTS
lung resident cell populations in Idiopathic Pulmonary Fibrosis. bioRxiv. https://doi.org/10.1101/ 759902. Habermann, A.C., Gutierrez, A.J., Bui, L.T., Yahn, S.L., Winters, N.I., Calvi, C.L., Peter, L., Chung, M.-I., Taylor, C.J., Jetter, C., et al. (2019). Singlecell RNA-sequencing reveals profibrotic roles of distinct epithelial and mesenchymal lineages in pulmonary fibrosis. bioRxiv. https://doi.org/10. 1101/753806. Liu, Z., Wu, H., Jiang, K., Wang, Y., Zhang, W., Chu, Q., Li, J., Huang, H., Cai, T., Ji, H., et al. (2016). MAPK-Mediated YAP Activation Controls Mechanical-Tension-Induced Pulmonary Alveolar Regeneration. Cell Rep. 16, 1810–1819.
REFERENCES
Minagawa, S., Araya, J., Numata, T., Nojiri, S., Hara, H., Yumino, Y., Kawaishi, M., Odaka, M., Morikawa, T., Nishimura, S.L., et al. (2011). Accelerated epithelial cell senescence in IPF and the inhibitory role of SIRT6 in TGF-b-induced senescence of human bronchial epithelial cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 300, L391–L401.
Adams, T.S., Schupp, J.C., Poli, S., Ayaub, E.A., Neumark, N., Ahangari, F., Chu, S.G., Raby, B.A., DeIuliis, G., Januszyk, M., et al. (2019). Single Cell RNA-seq reveals ectopic and aberrant
Plantier, L., Crestani, B., Wert, S.E., Dehoux, M., Zweytick, B., Guenther, A., and Whitsett, J.A. (2011). Ectopic respiratory epithelial cell differentiation in bronchiolised distal airspaces in idiopathic pulmonary fibrosis. Thorax 66, 651–657.
We thank members of the Kim lab and the many labs whose work could not be cited because of space limits. C.F.K. is supported in part by National Institutes of Health grants R01 HL132266 and R01 HL125821 and the Celgene IDEAL Consortium.
Reyfman, P.A., Walter, J.M., Joshi, N., Anekalla, K.R., McQuattie-Pimentel, A.C., Chiu, S., Fernandez, R., Akbarpour, M., Chen, C.-I., Ren, Z., et al. (2019). Single-Cell Transcriptomic Analysis of Human Lung Provides Insights into the Pathobiology of Pulmonary Fibrosis. Am. J. Respir. Crit. Care Med. 199, rccm.201712–2410OC. Wang, L., Yang, L., Debidda, M., Witte, D., and Zheng, Y. (2007). Cdc42 GTPase-activating protein deficiency promotes genomic instability and premature aging-like phenotypes. Proc. Natl. Acad. Sci. USA 104, 1248–1253. Wu, H., Yu, Y., Huang, H., Hu, Y., Fu, S., Wang, Z., Shi, M., Zhao, X., Yuan, J., Li, J., et al. (2020). Progressive Pulmonary Fibrosis Is Caused by Elevated Mechanical Tension on Alveolar Stem Cells. Cell 180, this issue, 107–121. Yao, C., Guan, X., Carraro, G., Parimon, T., Liu, X., Huang, G., Soukiasian, H.J., David, G., Weigt, S.S., Belperio, J.A., et al. (2019). Senescence of alveolar stem cells drives progressive pulmonary fibrosis. bioRxiv. https://doi.org/10.1101/820175. Zhang, R., Pan, Y., Fanelli, V., Wu, S., Luo, A.A., Islam, D., Han, B., Mao, P., Ghazarian, M., Zeng, W., et al. (2015). Mechanical Stress and the Induction of Lung Fibrosis via the Midkine Signaling Pathway. Am. J. Respir. Crit. Care Med. 192, 315–323.
Every Breath You Take: New Insights into Plant and Animal Oxygen Sensing Daniel J. Gibbs1,* and Michael J. Holdsworth2,** 1School
of Biosciences, University of Birmingham, Edgbaston, B15 2TT, UK of Biosciences, University of Nottingham, Loughborough, LE12 5RD, UK *Correspondence: [email protected] (D.J.G.), [email protected] (M.J.H.) https://doi.org/10.1016/j.cell.2019.10.043 2School
Responses to hypoxia are regulated by oxygen-dependent degradation of kingdom-specific proteins in animals and plants. Masson et al. (2019) identified and characterized the mammalian counterpart of an oxygen-sensing pathway previously only observed in plants. Alongside other recent findings identifying novel oxygen sensors, this provides new insights into oxygen-sensing origins and mechanisms in eukaryotes. Oxygen is essential to almost all life on earth, being required for respiration and a wide range of cellular biochemistry. Multicellular eukaryotes evolved in response to the oxidation events that increased oxygen levels during Earth history, and mechanisms for directly sensing and responding to oxygen avail-
ability are found broadly across taxa. In metazoan animals and higher plants, transcriptional responses to reduced oxygen (hypoxia) are achieved by oxygen-dependent degradation of transcription factors through analogous but mechanistically distinct post-translational modifications. A recent study published in Science
22 Cell 180, January 9, 2020 ª 2019 Elsevier Inc.
showed that an oxygen-sensing enzyme first described in plants is also present in humans, revealing a conserved mechanism that transduces responses to hypoxia in both kingdoms (Masson et al., 2019). In animals, gene expression in response to hypoxia is coordinated by