Portal de Periódicos da CAPES

Lung Pericytes and Resident Fibroblasts

2016; Elsevier BV; Volume: 186; Issue: 10 Linguagem: Inglês

10.1016/j.ajpath.2016.07.004

1525-2191

Luke Barron, Sina A. Gharib, Jeremy S. Duffield,

Chronic Obstructive Pulmonary Disease (COPD) Research

Pericytes, resident fibroblasts, and mesenchymal stem cells are poorly described cell populations. They have recently been characterized in much greater detail in rodent lungs and have been shown to play important roles in development, homeostasis, response to injury and pathogens, as well as recovery from damage. These closely related mesenchymal cell populations form extensive connections to the lung's internal structure, as well as its internal and external surfaces. They generate and remodel extracellular matrix, coregulate the vasculature, help maintain and restore the epithelium, and act as sentries for the immune system. In this review, we revisit these functions in light of significant advances in characterizing and tracking lung fibroblast populations in rodents. Lineage tracing experiments have mapped the heritage, identified functions that discriminate lung pericytes from resident fibroblasts, identified a subset of mesenchymal stem cells, and shown these populations to be the predominant progenitors of pathological fibroblasts and myofibroblasts in lung diseases. These findings point to the importance of resident lung mesenchymal populations as therapeutic targets in acute lung injury as well as fibrotic and degenerative diseases. Far from being passive and quiescent, pericytes and resident fibroblasts are busily sensing and responding, through diverse mechanisms, to changes in lung health and function. Pericytes, resident fibroblasts, and mesenchymal stem cells are poorly described cell populations. They have recently been characterized in much greater detail in rodent lungs and have been shown to play important roles in development, homeostasis, response to injury and pathogens, as well as recovery from damage. These closely related mesenchymal cell populations form extensive connections to the lung's internal structure, as well as its internal and external surfaces. They generate and remodel extracellular matrix, coregulate the vasculature, help maintain and restore the epithelium, and act as sentries for the immune system. In this review, we revisit these functions in light of significant advances in characterizing and tracking lung fibroblast populations in rodents. Lineage tracing experiments have mapped the heritage, identified functions that discriminate lung pericytes from resident fibroblasts, identified a subset of mesenchymal stem cells, and shown these populations to be the predominant progenitors of pathological fibroblasts and myofibroblasts in lung diseases. These findings point to the importance of resident lung mesenchymal populations as therapeutic targets in acute lung injury as well as fibrotic and degenerative diseases. Far from being passive and quiescent, pericytes and resident fibroblasts are busily sensing and responding, through diverse mechanisms, to changes in lung health and function. The architecture of the lungs juxtaposes a large external surface area with an extensive vascular bed for efficient gas exchange. In between these epithelial and endothelial layers lies an elastic matrix, lymphatics, smooth muscle, resident and migratory leukocytes, as well as a poorly characterized population of mesenchymal stromal cells.1Morrisey E.E. Hogan B.L. Preparing for the first breath: genetic and cellular mechanisms in lung development.Dev Cell. 2010; 18: 8-23Abstract Full Text Full Text PDF PubMed Scopus (656) Google Scholar Many of these cells have been described to contribute to normal lung function, as well as loss of function, in disease states. This review focuses on the pleiotropic roles played by two distinct lung mesenchymal populations, known as pericytes and resident fibroblasts, that until now have been challenging to identify. We will describe their roles during development, homeostasis, and fibrotic diseases. New discoveries made by lineage tracing, conditional ablation, and targeted gene deletion of mesenchymal cell subpopulations, in rodents, have expanded on and reinforced the conclusion that mesenchymal fibroblasts are crucial for forming and maintaining vascular networks, sensing damage, recruiting inflammatory cells, and remodeling the extracellular matrix of the lung and other organs. These actions are beneficial when maintaining or returning a tissue to homeostasis, but can become pathological when prolonged, excessive, or recurrent. Injuries, infections, and cellular damage provoke differentiation of resident mesenchymal cells into activated or pathological fibroblasts that drive inflammation, deposit new extracellular matrix, and withdraw their support from endothelial cells. When pathological fibroblasts additionally express the contractile protein α-smooth muscle actin (α-SMA) they are known as myofibroblasts. Persistent myofibroblast activation can cumulate in fibrosis with progressive scarring, loss of lung function, morbidity, and mortality. Pericytes are mesenchymal cells closely related to vascular smooth muscle cells (VSMCs) that underlie and envelop capillaries, forming focal contacts with adjacent endothelial cells. Pericytes may be strictly defined anatomically by the presence of processes within capillary basement membrane (Figure 1). They may also be distinguished by molecular criteria, including the lack of leukocyte, endothelial, and parenchymal hallmarks, and the presence of markers, including platelet-derived growth factor (PDGF) receptors, and, often, proteoglycan neural/glial antigen 2 (NG2; alias chondroitin sulfate proteoglycan-4).2Armulik A. Abramsson A. Betsholtz C. Endothelial/pericyte interactions.Circ Res. 2005; 97: 512-523Crossref PubMed Scopus (1531) Google Scholar, 3Armulik A. Genove G. Betsholtz C. Pericytes: developmental, physiological, and pathological perspectives, problems, and promises.Dev Cell. 2011; 21: 193-215Abstract Full Text Full Text PDF PubMed Scopus (1722) Google Scholar, 4Weibel E.R. On pericytes, particularly their existence on lung capillaries.Microvasc Res. 1974; 8: 218-235Crossref PubMed Scopus (114) Google Scholar, 5Kloc M. Kubiak J.Z. Li X.C. Ghobrial R.M. Pericytes, microvasular dysfunction, and chronic rejection.Transplantation. 2015; 99: 658-667Crossref PubMed Scopus (19) Google Scholar Pericytes embed themselves within the capillary basement membrane and may extend peg-socket contacts with the endothelium ending in adherence, gap, and tight junctions between each pericyte and one or more endothelial cells.2Armulik A. Abramsson A. Betsholtz C. Endothelial/pericyte interactions.Circ Res. 2005; 97: 512-523Crossref PubMed Scopus (1531) Google Scholar, 3Armulik A. Genove G. Betsholtz C. Pericytes: developmental, physiological, and pathological perspectives, problems, and promises.Dev Cell. 2011; 21: 193-215Abstract Full Text Full Text PDF PubMed Scopus (1722) Google Scholar, 4Weibel E.R. On pericytes, particularly their existence on lung capillaries.Microvasc Res. 1974; 8: 218-235Crossref PubMed Scopus (114) Google Scholar, 5Kloc M. Kubiak J.Z. Li X.C. Ghobrial R.M. Pericytes, microvasular dysfunction, and chronic rejection.Transplantation. 2015; 99: 658-667Crossref PubMed Scopus (19) Google Scholar, 6Rowley J.E. Johnson J.R. Pericytes in chronic lung disease.Int Arch Allergy Immunol. 2014; 164: 178-188Crossref PubMed Scopus (28) Google Scholar The extent of pericyte vascular coverage varies by organ and anatomy and is relatively high in the lung, correlating with a stronger barrier and lower turnover of endothelial cells.3Armulik A. Genove G. Betsholtz C. Pericytes: developmental, physiological, and pathological perspectives, problems, and promises.Dev Cell. 2011; 21: 193-215Abstract Full Text Full Text PDF PubMed Scopus (1722) Google Scholar The lung also contains a second resident mesenchymal population with similar morphology and shared expression of key markers. These resident fibroblasts descend from different precursors and position themselves beneath epithelial cells or are scattered through the interstitium between the epithelial and endothelial layers, but without directly contacting the vasculature.7Kapanci Y. Ribaux C. Chaponnier C. Gabbiani G. Cytoskeletal features of alveolar myofibroblasts and pericytes in normal human and rat lung.J Histochem Cytochem. 1992; 40: 1955-1963Crossref PubMed Scopus (84) Google Scholar, 8Zhang W. Menke D.B. Jiang M. Chen H. Warburton D. Turcatel G. Lu C.H. Xu W. Luo Y. Shi W. Spatial-temporal targeting of lung-specific mesenchyme by a Tbx4 enhancer.BMC Biol. 2013; 11: 111Crossref PubMed Scopus (55) Google Scholar, 9Rock J.R. Barkauskas C.E. Cronce M.J. Xue Y. Harris J.R. Liang J. Noble P.W. Hogan B.L. Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition.Proc Natl Acad Sci U S A. 2011; 108: E1475-E1483Crossref PubMed Scopus (691) Google Scholar, 10Hung C. Linn G. Chow Y.H. Kobayashi A. Mittelsteadt K. Altemeier W.A. Gharib S.A. Schnapp L.M. Duffield J.S. Role of lung pericytes and resident fibroblasts in the pathogenesis of pulmonary fibrosis.Am J Respir Crit Care Med. 2013; 188: 820-830Crossref PubMed Scopus (252) Google Scholar, 11Bostrom H. Willetts K. Pekny M. Leveen P. Lindahl P. Hedstrand H. Pekna M. Hellstrom M. Gebre-Medhin S. Schalling M. Nilsson M. Kurland S. Tornell J. Heath J.K. Betsholtz C. PDGF-A signaling is a critical event in lung alveolar myofibroblast development and alveogenesis.Cell. 1996; 85: 863-873Abstract Full Text Full Text PDF PubMed Scopus (694) Google Scholar Together, pericytes and other fibroblasts constitute 10% to 20% of all lung cells, and both populations differentiate into matrix-generating activated myofibroblasts.9Rock J.R. Barkauskas C.E. Cronce M.J. Xue Y. Harris J.R. Liang J. Noble P.W. Hogan B.L. Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition.Proc Natl Acad Sci U S A. 2011; 108: E1475-E1483Crossref PubMed Scopus (691) Google Scholar, 10Hung C. Linn G. Chow Y.H. Kobayashi A. Mittelsteadt K. Altemeier W.A. Gharib S.A. Schnapp L.M. Duffield J.S. Role of lung pericytes and resident fibroblasts in the pathogenesis of pulmonary fibrosis.Am J Respir Crit Care Med. 2013; 188: 820-830Crossref PubMed Scopus (252) Google Scholar However, they are also heterogeneous and plastic populations, which has complicated their study and contributed to contrasting interpretations of their role in fibrotic lung diseases.2Armulik A. Abramsson A. Betsholtz C. Endothelial/pericyte interactions.Circ Res. 2005; 97: 512-523Crossref PubMed Scopus (1531) Google Scholar, 3Armulik A. Genove G. Betsholtz C. Pericytes: developmental, physiological, and pathological perspectives, problems, and promises.Dev Cell. 2011; 21: 193-215Abstract Full Text Full Text PDF PubMed Scopus (1722) Google Scholar, 6Rowley J.E. Johnson J.R. Pericytes in chronic lung disease.Int Arch Allergy Immunol. 2014; 164: 178-188Crossref PubMed Scopus (28) Google Scholar, 9Rock J.R. Barkauskas C.E. Cronce M.J. Xue Y. Harris J.R. Liang J. Noble P.W. Hogan B.L. Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition.Proc Natl Acad Sci U S A. 2011; 108: E1475-E1483Crossref PubMed Scopus (691) Google Scholar, 10Hung C. Linn G. Chow Y.H. Kobayashi A. Mittelsteadt K. Altemeier W.A. Gharib S.A. Schnapp L.M. Duffield J.S. Role of lung pericytes and resident fibroblasts in the pathogenesis of pulmonary fibrosis.Am J Respir Crit Care Med. 2013; 188: 820-830Crossref PubMed Scopus (252) Google Scholar, 12Kendall R.T. Feghali-Bostwick C.A. Fibroblasts in fibrosis: novel roles and mediators.Front Pharmacol. 2014; 5: 123Crossref PubMed Scopus (555) Google Scholar, 13Noble P.W. Barkauskas C.E. Jiang D. Pulmonary fibrosis: patterns and perpetrators.J Clin Invest. 2012; 122: 2756-2762Crossref PubMed Scopus (341) Google Scholar, 14Hinz B. Phan S.H. Thannickal V.J. Prunotto M. Desmouliere A. Varga J. De Wever O. Mareel M. Gabbiani G. 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Cell plasticity in lung injury and repair: report from an NHLBI workshop, April 19-20, 2010.Proc Am Thorac Soc. 2011; 8: 215-222Crossref PubMed Scopus (33) Google Scholar Such broad adaptability is proposed to enable pericytes and resident fibroblasts to repeatedly adjust to support growing, injured, or regenerating vascular or airway structures.2Armulik A. Abramsson A. Betsholtz C. Endothelial/pericyte interactions.Circ Res. 2005; 97: 512-523Crossref PubMed Scopus (1531) Google Scholar, 6Rowley J.E. Johnson J.R. Pericytes in chronic lung disease.Int Arch Allergy Immunol. 2014; 164: 178-188Crossref PubMed Scopus (28) Google Scholar, 13Noble P.W. Barkauskas C.E. Jiang D. Pulmonary fibrosis: patterns and perpetrators.J Clin Invest. 2012; 122: 2756-2762Crossref PubMed Scopus (341) Google Scholar Extensive investigation into the origins of pathogenic myofibroblasts identified three other candidates, hematopoietic fibrocytes and reprogrammed epithelial or endothelial cells.2Armulik A. Abramsson A. Betsholtz C. Endothelial/pericyte interactions.Circ Res. 2005; 97: 512-523Crossref PubMed Scopus (1531) Google Scholar, 13Noble P.W. Barkauskas C.E. Jiang D. Pulmonary fibrosis: patterns and perpetrators.J Clin Invest. 2012; 122: 2756-2762Crossref PubMed Scopus (341) Google Scholar Although these types of cells can assume a myofibroblast identity, key lineage-tracing experiments demonstrate that the pericytes and resident fibroblasts are the predominant source of myofibroblasts in the lung during development, in its mature healthy state, and after injury.2Armulik A. Abramsson A. Betsholtz C. Endothelial/pericyte interactions.Circ Res. 2005; 97: 512-523Crossref PubMed Scopus (1531) Google Scholar, 9Rock J.R. Barkauskas C.E. Cronce M.J. Xue Y. Harris J.R. Liang J. Noble P.W. Hogan B.L. Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition.Proc Natl Acad Sci U S A. 2011; 108: E1475-E1483Crossref PubMed Scopus (691) Google Scholar, 10Hung C. Linn G. Chow Y.H. Kobayashi A. Mittelsteadt K. Altemeier W.A. Gharib S.A. Schnapp L.M. Duffield J.S. Role of lung pericytes and resident fibroblasts in the pathogenesis of pulmonary fibrosis.Am J Respir Crit Care Med. 2013; 188: 820-830Crossref PubMed Scopus (252) Google Scholar, 13Noble P.W. Barkauskas C.E. Jiang D. Pulmonary fibrosis: patterns and perpetrators.J Clin Invest. 2012; 122: 2756-2762Crossref PubMed Scopus (341) Google Scholar Pericytes and resident lung fibroblasts can be identified independently of their location, with appropriate criteria for excluding other cell types, by their expression of markers, including PDGF receptor (PDGFR) β and α, CD146, NG2, α-SMA, collagen I(α)1 (Col1), vimentin, and desmin (Table 1).2Armulik A. Abramsson A. Betsholtz C. 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Talati M. Helm K. Alford C.E. Kropski J.A. Loyd J. Wheeler L. Johnson J. Austin E. Nozik-Grayck E. Meyrick B. West J.D. Klemm D.J. Majka S.M. ABCG2pos lung mesenchymal stem cells are a novel pericyte subpopulation that contributes to fibrotic remodeling.Am J Physiol Cell Physiol. 2014; 307: C684-C698Crossref PubMed Scopus (62) Google ScholarTable 1Expression Patterns of Markers for Pericytes and Resident Fibroblasts in Normal Adult Lung Tissue (Mainly from Rodent Studies)MarkerPericytesResident fibroblastsOther cell typesReferencesPDGFR-β+−Vascular smooth muscle2Armulik A. Abramsson A. Betsholtz C. Endothelial/pericyte interactions.Circ Res. 2005; 97: 512-523Crossref PubMed Scopus (1531) Google Scholar, 3Armulik A. Genove G. Betsholtz C. Pericytes: developmental, physiological, and pathological perspectives, problems, and promises.Dev Cell. 2011; 21: 193-215Abstract Full Text Full Text PDF PubMed Scopus (1722) Google Scholar, 5Kloc M. Kubiak J.Z. Li X.C. Ghobrial R.M. Pericytes, microvasular dysfunction, and chronic rejection.Transplantation. 2015; 99: 658-667Crossref PubMed Scopus (19) Google Scholar, 9Rock J.R. Barkauskas C.E. Cronce M.J. Xue Y. Harris J.R. Liang J. Noble P.W. Hogan B.L. Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition.Proc Natl Acad Sci U S A. 2011; 108: E1475-E1483Crossref PubMed Scopus (691) Google Scholar, 10Hung C. Linn G. Chow Y.H. Kobayashi A. Mittelsteadt K. Altemeier W.A. Gharib S.A. Schnapp L.M. Duffield J.S. Role of lung pericytes and resident fibroblasts in the pathogenesis of pulmonary fibrosis.Am J Respir Crit Care Med. 2013; 188: 820-830Crossref PubMed Scopus (252) Google Scholar, 18Gaengel K. Genove G. Armulik A. Betsholtz C. Endothelial-mural cell signaling in vascular development and angiogenesis.Arterioscler Thromb Vasc Biol. 2009; 29: 630-638Crossref PubMed Scopus (637) Google Scholar, 19Hellstrom M. Kalen M. Lindahl P. Abramsson A. 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Dynamic regulation of platelet-derived growth factor receptor alpha expression in alveolar fibroblasts during realveolarization.Am J Respir Cell Mol Biol. 2012; 47: 517-527Crossref PubMed Scopus (110) Google ScholarNG2+/−−Macrophages2Armulik A. Abramsson A. Betsholtz C. Endothelial/pericyte interactions.Circ Res. 2005; 97: 512-523Crossref PubMed Scopus (1531) Google Scholar, 3Armulik A. Genove G. Betsholtz C. Pericytes: developmental, physiological, and pathological perspectives, problems, and promises.Dev Cell. 2011; 21: 193-215Abstract Full Text Full Text PDF PubMed Scopus (1722) Google Scholar, 5Kloc M. Kubiak J.Z. Li X.C. Ghobrial R.M. Pericytes, microvasular dysfunction, and chronic rejection.Transplantation. 2015; 99: 658-667Crossref PubMed Scopus (19) Google Scholar, 9Rock J.R. Barkauskas C.E. Cronce M.J. Xue Y. Harris J.R. Liang J. Noble P.W. Hogan B.L. Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition.Proc Natl Acad Sci U S A. 2011; 108: E1475-E1483Crossref PubMed Scopus (691) Google Scholar, 10Hung C. Linn G. Chow Y.H. Kobayashi A. Mittelsteadt K. Altemeier W.A. Gharib S.A. Schnapp L.M. Duffield J.S. Role of lung pericytes and resident fibroblasts in the pathogenesis of pulmonary fibrosis.Am J Respir Crit Care Med. 2013; 188: 820-830Crossref PubMed Scopus (252) Google Scholar, 17Marriott S. Baskir R.S. Gaskill C. Menon S. Carrier E.J. Williams J. Talati M. Helm K. Alford C.E. Kropski J.A. Loyd J. Wheeler L. Johnson J. Austin E. Nozik-Grayck E. Meyrick B. West J.D. Klemm D.J. Majka S.M. ABCG2pos lung mesenchymal stem cells are a novel pericyte subpopulation that contributes to fibrotic remodeling.Am J Physiol Cell Physiol. 2014; 307: C684-C698Crossref PubMed Scopus (62) Google Scholar, 20Kramann R. Schneider R.K. DiRocco D.P. Machado F. Fleig S. Bondzie P.A. Henderson J.M. Ebert B.L. Humphreys B.D. Perivascular Gli1+ progenitors are key contributors to injury-induced organ fibrosis.Cell Stem Cell. 2015; 16: 51-66Abstract Full Text Full Text PDF PubMed Scopus (594) Google Scholar, 23Stark K. Eckart A. Haidari S. Tirniceriu A. Lorenz M. von Bruhl M.L. Gartner F. Khandoga A.G. Legate K.R. Pless R. Hepper I. Lauber K. Walzog B. Massberg S. Capillary and arteriolar pericytes attract innate leukocytes exiting through venules and “instruct” them with pattern-recognition and motility programs.Nat Immunol. 2013; 14: 41-51Crossref PubMed Scopus (300) Google Scholarα-SMA+/−−Vascular, bronchiolar smooth muscle5Kloc M. Kubiak J.Z. Li X.C. Ghobrial R.M. Pericytes, microvasular dysfunction, and chronic rejection.Transplantation. 2015; 99: 658-667Crossref PubMed Scopus (19) Google Scholar, 9Rock J.R. Barkauskas C.E. Cronce M.J. Xue Y. Harris J.R. Liang J. Noble P.W. Hogan B.L. 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