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Mesenchymal Regulation of the Microvascular Niche in Chronic Lung Diseases

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The adult lung is comprised of diverse vascular, epithelial, and mesenchymal progenitor cell populations that reside in distinct niches. Mesenchymal progenitor cells (MPCs) are intimately associated with both the epithelium and the vasculature, and new evidence is emerging to describe their functional roles in these niches. Also emerging, following lineage analysis and single cell sequencing, is a new understanding of the diversity of mesenchymal cell subpopulations in the lung. However, several gaps in knowledge remain, including how newly defined MPC lineages interact with cells in the vascular niche and the role of adult lung MPCs during lung repair and regeneration following injury, especially in chronic lung diseases. Here we summarize how the current evidence on MPC regulation of the microvasculature during tissue homeostasis and injury may inform studies on understanding their role in chronic lung disease pathogenesis or repair. © 2019 American Physiological Society. Compr Physiol 9:1431‐1441, 2019.

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Figure 1. Figure 1. The pulmonary microvascular niche. During tissue homeostasis, cells that comprise the microvascular niche are intimately associated and include microvascular endothelial cells (MVECs, pink), pericyte/vascular smooth muscle cells (vSMCs, red), mesenchymal progenitor cells (MPCs, green), fibroblasts (FB, purple), and alveolar epithelial cells (AECs, yellow). Dysfunction in one or more of these cell types, here specifically MPCs, impacts vascular homeostasis and remodeling. Following injury or during disease remodeling is also complex and may be described as (1) involving MVEC, SMC, or fibroblast proliferation; (2) loss of differentiated SMC phenotypes with mesenchymal proliferation; and/or (3) loss of microvessel structures or rarefaction.
Figure 2. Figure 2. A comparison of MPC, pericytes, and fibroblasts.
Figure 3. Figure 3. Summary of common gene expression signatures associated with Wnt signaling and angiogenesis in ABCG2pos MPC from COPD, IPF, and PAH patients.

Figure 1. The pulmonary microvascular niche. During tissue homeostasis, cells that comprise the microvascular niche are intimately associated and include microvascular endothelial cells (MVECs, pink), pericyte/vascular smooth muscle cells (vSMCs, red), mesenchymal progenitor cells (MPCs, green), fibroblasts (FB, purple), and alveolar epithelial cells (AECs, yellow). Dysfunction in one or more of these cell types, here specifically MPCs, impacts vascular homeostasis and remodeling. Following injury or during disease remodeling is also complex and may be described as (1) involving MVEC, SMC, or fibroblast proliferation; (2) loss of differentiated SMC phenotypes with mesenchymal proliferation; and/or (3) loss of microvessel structures or rarefaction.

Figure 2. A comparison of MPC, pericytes, and fibroblasts.

Figure 3. Summary of common gene expression signatures associated with Wnt signaling and angiogenesis in ABCG2pos MPC from COPD, IPF, and PAH patients.
 1.Abbuehl J‐P, Tatarova Z, Held W, Huelsken J. Long‐term engraftment of primary bone marrow stromal cells repairs niche damage and improves hematopoietic stem cell transplantation. Cell Stem Cell 21: 241‐255.e246, 2017.
 2.Aliotta JM, Pereira M, Wen S, Dooner MS, Del Tatto M, Papa E, Goldberg LR, Baird GL, Ventetuolo CE, Quesenberry PJ, Klinger JR. Exosomes induce and reverse monocrotaline‐induced pulmonary hypertension in mice. Cardiovasc Res 110: 319‐330, 2016.
 3.Alt E, Yan Y, Gehmert S, Song Y‐H, Altman A, Gehmert S, Vykoukal D, Bai X. Fibroblasts share mesenchymal phenotypes with stem cells, but lack their differentiation and colony‐forming potential. Biol Cell 103: 197‐208, 2011.
 4.Antony VB, Thannickal VJ. Cellular senescence in chronic obstructive pulmonary disease: Multifaceted and multifunctional. Am J Respir Cell Mol Biol 59: 135‐136, 2018.
 5.Armulik A, Abramsson A, Betsholtz C. Endothelial/pericyte interactions. Circ Res 97: 512‐523, 2005.
 6.Armulik A, Genov G, Betsholtz C. Pericytes: Developmental, physiological, and pathological perspectives, problems, and promises. Dev Cell 21: 193‐215, 2011.
 7.Aslam M, Baveja R, Liang OD, Fernandez‐Gonzalez A, Lee C, Mitsialis SA, Kourembanas S. Bone marrow stromal cells attenuate lung injury in a murine model of neonatal chronic lung disease. Am J Respir Crit Care Med 180: 1122‐1130, 2009.
 8.Austin ED, Kawut SM, Gladwin MT, Abman SH. Pulmonary hypertension: NHLBI workshop on the primary prevention of chronic lung diseases. Ann Am Thorac Soc 11: S178‐S185, 2014.
 9.Baber SR, Deng W, Master RG, Bunnell BA, Taylor BK, Murthy SN, Hyman AL, Kadowitz PJ. Intratracheal mesenchymal stem cell administration attenuates monocrotaline‐induced pulmonary hypertension and endothelial dysfunction. Am J Physiol Heart Circ Physiol 292: H1120‐H1128, 2007.
 10.Banerji S, Ni J, Wang S‐X, Clasper S, Su J, Tammi R, Jones M, Jackson DG. LYVE‐1, a new homologue of the CD44 glycoprotein, is a lymph‐specific receptor for hyaluronan. J Cell Biol 144: 789‐801, 1999.
 11.Barratt S, Millar A. Vascular remodelling in the pathogenesis of idiopathic pulmonary fibrosis. QJM 107: 515‐519, 2014.
 12.Barron L, Gharib SA, Duffield JS. Lung pericytes and resident fibroblasts: Busy multitaskers. Am J Pathol 186: 2519‐2531, 2016.
 13.Baskir R, Majka S. Pulmonary vascular remodeling by resident lung stem and progenitor cells. In: Firth A, Yuan JXJ, editors. Lung Stem Cells in the Epithelium and Vasculature. Springer International Publishing, 2015, p. 221‐240.
 14.Battula VL, Evans KW, Hollier BG, Shi Y, Marini FC, Ayyanan A, Wang R‐Y, Brisken C, Guerra R, Andreeff M, Mani SA. Epithelial‐mesenchymal transition‐derived cells exhibit multilineage differentiation potential similar to mesenchymal stem cells. Stem Cells 28: 1435‐1445, 2010.
 15.Beckermann BM, Kallifatidis G, Groth A, Frommhold D, Apel A, Mattern J, Salnikov AV, Moldenhauer G, Wagner W, Diehlmann A, Saffrich R, Schubert M, Ho AD, Giese N, Buchler MW, Friess H, Buchler P, Herr I. VEGF expression by mesenchymal stem cells contributes to angiogenesis in pancreatic carcinoma. Br J Cancer 99: 622, 2008.
 16.Beers MF ME. The three R's of lung health and disease: Repair, remodeling, and regeneration. J Clin Invest 121: 2065‐2073, 2011.
 17.Berger M, Bergers G, Arnold B, Hämmerling GJ, Ganss R. Regulator of G‐protein signaling‐5 induction in pericytes coincides with active vessel remodeling during neovascularization. Blood 105: 1094‐1101, 2004.
 18.Birbrair A, Zhang T, Files D, Mannava S, Smith T, Wang Z‐M, Messi M, Mintz A, Delbono O. Type‐1 pericytes accumulate after tissue injury and produce collagen in an organ‐dependent manner. Stem Cell Res Ther 5: 122, 2014.
 19.Blocki A, Wang Y, Koch M, Peh P, Beyer S, Law P, Hui J, Raghunath M. Not all MSCs can act as pericytes: Functional in vitro assays to distinguish pericytes from other mesenchymal stem cells in angiogenesis. Stem Cells Dev 22: 2347‐2355, 2013.
 20.Bonner JC. Regulation of PDGF and its receptors in fibrotic diseases. Cytokine Growth Factor Rev 15: 255‐273, 2004.
 21.Bustos ML, Huleihel L, Kapetanaki MG, Lino‐Cardenas CL, Mroz L, Ellis BM, McVerry BJ, Richards TJ, Kaminski N, Cerdenes N, Mora AL, Rojas M. Aging mesenchymal stem cells fail to protect because of impaired migration and antiinflammatory response. Am J Respir Crit Care Med 189: 787‐798, 2014.
 22.Buttler K, Kreysing A, von Kaisenberg CS, Schweigerer L, Gale N, Papoutsi M, Wilting J. Mesenchymal cells with leukocyte and lymphendothelial characteristics in murine embryos. Dev Dyn 235: 1554‐1562, 2006.
 23.Cardenes N, Alvarez D, Sellares J, Peng Y, Corey C, Wecht S, Nouraie SM, Shanker S, Sembrat J, Bueno M, Shiva S, Mora AL, Rojas M. Senescence of bone marrow‐derived mesenchymal stem cells from patients with idiopathic pulmonary fibrosis. Stem Cell Res Ther 9: 257, 2018.
 24.Carmeliet P. Mechanisms of angiogenesis and arteriogenesis. Nat Med 6: 389‐395, 2000.
 25.Chang YS, di Tomaso E, McDonald DM, Jones R, Jain RK, Munn LL. Mosaic blood vessels in tumors: Frequency of cancer cells in contact with flowing blood. Proc Natl Acad Sci 97: 14608‐14613, 2000.
 26.Chen S, Chen X, Wu X, Wei S, Han W, Lin J, Kang M, Chen L. Hepatocyte growth factor‐modified mesenchymal stem cells improve ischemia/reperfusion‐induced acute lung injury in rats. Gene Ther 24: 3‐11, 2017.
 27.Chhabra P, Brayman KL. The use of stem cells in kidney disease. Curr Opin Organ Transplant 14: 72‐78, 2009.
 28.Chow K, Fessel JP, KaoriIhida S, Schmidt EP, Gaskill C, Alvarez D, Graham B, Harrison DG, Wagner DH, Nozik‐Grayck E, West JD, Klemm DJ, Majka SM. Dysfunctional resident lung mesenchymal stem cells contribute to pulmonary microvascular remodeling. Pulmonary Circulation 3: 31‐49, 2013.
 29.Condliffe R, Howard LS. Connective tissue disease‐associated pulmonary arterial hypertension. F1000Prime Rep 7: 06, 2015.
 30.Conrad C, Niess H, Huss R, Huber S, von Luettichau I, Nelson PJ, Ott HC, Jauch K‐W, Bruns CJ. Multipotent mesenchymal stem cells acquire a lymphendothelial phenotype and enhance lymphatic regeneration in vivo. Circulation 119: 281, 2009.
 31.Cottin V, Nunes H, Mouthon L, Gamondes D, Lazor R, Hachulla E, Revel D, Valeyre D, Cordier J‐F, Groupe d'Etudes et de Recherche sur les Maladies “Orphelines” Pulmonaires. Combined pulmonary fibrosis and emphysema syndrome in connective tissue disease. Arthritis Rheum 63: 295‐304, 2011.
 32.Crisan M, Yap S, Casteilla L, Chen C‐W, Corselli M, Park TS, Andriolo G, Sun B, Zheng B, Zhang L, Norotte C, Teng P‐N, Traas J, Schugar R, Deasy BM, Badylak S, Bűhring H‐J, Giacobino J‐P, Lazzari L, Huard J, Péault B. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 3: 301‐313, 2008.
 33.Crocker DJ, Murad TM, Geer JC. Role of the pericyte in wound healing: An ultrastructural study. Exp Mol Pathol 13: 51‐65, 1970.
 34.Cuttica MJ, Langenickel T, Noguchi A, Machado RF, Gladwin MT, Boehm M. Perivascular T‐cell infiltration leads to sustained pulmonary artery remodeling after endothelial cell damage. Am J Respir Cell Mol Biol 45: 62‐71, 2011.
 35.Duffield JS. The elusive source of myofibroblasts: Problem solved? Nat Med 18: 1178‐1180, 2012.
 36.Dufourcq P, Descamps B, Tojais NF, Leroux L, Oses P, Daret D, Moreau C, Lamazière J‐MD, Couffinhal T, Duplàa C. Secreted Frizzled‐related protein‐1 enhances mesenchymal stem cell function in angiogenesis and contributes to Neovessel maturation. Stem Cells 26: 2991‐3001, 2008.
 37.Dulmovits BM, Herman IM. Microvascular remodeling and wound healing: A role for pericytes. Int J Biochem Cell Biol 44: 1800‐1812, 2012.
 38.El Agha E, Kramann R, Schneider RK, Li X, Seeger W, Humphreys BD, Bellusci S. Mesenchymal stem cells in fibrotic disease. Cell Stem Cell 21: 166‐177.
 39.Firth AL, Yao W, Ogawa A, Madani MM, Lin GY, Yuan JXJ. Multipotent mesenchymal progenitor cells are present in endarterectomized tissues from patients with chronic thromboembolic pulmonary hypertension. Am J Physiol Cell Physiol 298: C1217‐C1225, 2010.
 40.Folberg R, Hendrix MJC, Maniotis AJ. Vasculogenic mimicry and tumor angiogenesis. Am J Pathol 156: 361‐381, 2000.
 41.Friedenstein AJ, Petrakova KV, Kurolesova AI, Frolova GP. Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation 6: 230‐247, 1968.
 42.Gaskill C, Majka SM. A high‐yield isolation and enrichment strategy for human lung microvascular endothelial cells. Pulm Circ 7: 108‐116, 2017.
 43.Gaskill C, Marriott S, Pratap S, Menon S, Hedges LK, Fessel JP, Kropski JA, Ames D, Wheeler L, Loyd JE, Hemnes AR, Roop DR, Klemm DJ, Austin ED, Majka SM. Shared gene expression patterns in mesenchymal progenitors derived from lung and epidermis in pulmonary arterial hypertension: Identifying key pathways in pulmonary vascular disease. Pulmonary Circulation 6: 483‐497, 2016.
 44.Gaskill CF, Carrier EJ, Kropski JA, Bloodworth NC, Menon S, Foronjy RF, Taketo MM, Hong CC, Austin ED, West JD, Means AL, Loyd JE, Merryman WD, Hemnes AR, De Langhe S, Blackwell TS, Klemm DJ, Majka SM. Disruption of lineage specification in adult pulmonary mesenchymal progenitor cells promotes microvascular dysfunction. J Clin Invest 127: 2017.
 45.Gatti S, Bruno S, Deregibus MC, Sordi A, Cantaluppi V, Tetta C, Camussi G. Microvesicles derived from human adult mesenchymal stem cells protect against ischaemia‐reperfusion‐induced acute and chronic kidney injury. Nephrol Dial Transplant 26: 1474‐1483, 2011.
 46.Geiger S, Hirsch D, Hermann FG. Cell therapy for lung disease. Eur Respir Rev 26: 2017.
 47.Gu B, Alexander JS, Gu Y, Zhang Y, Lewis DF, Wang Y. Expression of lymphatic vascular endothelial hyaluronan receptor‐1 (LYVE‐1) in the human placenta. Lymphat Res Biol 4: 11‐17, 2006.
 48.Guimaraes‐Camboa N, Cattaneo P, Sun Y, Moore‐Morris T, Gu Y, Dalton ND, Rockenstein E, Masliah E, Peterson KL, Stallcup WB, Chen J, Evans SM. Pericytes of multiple organs do not behave as mesenchymal stem cells in vivo. Cell Stem Cell 20: 345‐359.e345, 2017.
 49.Gupta N, Su X, Popov B, Lee JW, Serikov V, Matthay MA. Intrapulmonary delivery of bone marrow‐derived mesenchymal stem cells improves survival and attenuates endotoxin‐induced acute lung injury in mice. J Immunol 179: 1855‐1863, 2007.
 50.Han J, Lu X, Zou L, Xu X, Qiu H. E‐prostanoid 2 receptor overexpression promotes mesenchymal stem cell attenuated lung injury. Hum Gene Ther 27: 621‐630, 2016.
 51.Hanumegowda C, Farkas L, Kolb M. Angiogenesis in pulmonary fibrosis: Too much or not enough? Chest 142: 200‐207, 2012.
 52.Hashimoto N, Jin H, Liu T, Chensue SW, Phan SH. Bone marrow‐derived progenitor cells in pulmonary fibrosis. J Clin Invest 113: 243‐252, 2004.
 53.Hellstrom M, Gerhardt H, Kalen M, Li X, Eriksson U, Wolburg H, Betsholtz C. Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J Cell Biol 153: 543‐554, 2001.
 54.Hirschi KK, D'Amore PA. Pericytes in the microvasculature. Cardiovasc Res 32: 687‐698, 1996.
 55.Hofer HR, Tuan RS. Secreted trophic factors of mesenchymal stem cells support neurovascular and musculoskeletal therapies. Stem cell Res Ther 7: 131, 2016.
 56.Hong Y, Kim YS, Hong SH, Oh YM. Therapeutic effects of adipose‐derived stem cells pretreated with pioglitazone in an emphysema mouse model. Exp Mol Med 48: e266, 2016.
 57.Hopkins N, McLoughlin P. The structural basis of pulmonary hypertension in chronic lung disease: Remodelling, rarefaction or angiogenesis? J Anat 201: 335‐348, 2002.
 58.Hung C, Linn G, Chow Y‐H, Kobayashi A, Mittelsteadt K, Altemeier WA, Gharib SA, Schnapp LM, Duffield JS. Role of lung pericytes and resident fibroblasts in the pathogenesis of pulmonary fibrosis. Am J Respir Crit Care Med 188: 820‐830, 2013.
 59.Islam MN, Das SR, Emin MT, Wei M, Sun L, Westphalen K, Rowlands DJ, Quadri SK, Bhattacharya S, Bhattacharya J. Mitochondrial transfer from bone‐marrow‐derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat Med 18: 759‐765, 2012.
 60.Jackson KA, Majka SM, Wang H, Pocius J, Hartley CJ, Majesky MW, Entman ML, Michael LH, Hirschi KK, Goodell MA. Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J Clin Invest 107: 1395‐1402, 2001.
 61.Jun D, Garat C, West J, Thorn N, Chow K, Cleaver T, Sullivan T, Torchia EC, Childs C, Shade T, Tadjali M, Lara A, Nozik‐Grayck E, Malkoski S, Sorrentino B, Meyrick B, Klemm D, Rojas M, Wagner DH, Majka SM. The pathology of bleomycin‐induced fibrosis is associated with loss of resident lung mesenchymal stem cells that regulate effector T‐cell proliferation. Stem Cells 29: 725‐735, 2011.
 62.Karunamuni G, Yang K, Doughman YQ, Wikenheiser J, Bader D, Barnett J, Austin A, Parsons‐Wingerter P, Watanabe M. Expression of lymphatic markers during avian and mouse cardiogenesis. Anat Rec (Hoboken) 293: 259‐270, 2010.
 63.Kasahara Y, Tuder RM, Cool CD, Lynch DA, Flores SC, Voelkel NF. Endothelial cell death and decreased expression of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in emphysema. Am J Respir Crit Care Med 163: 737‐744, 2001.
 64.Keane MP. Angiogenesis and pulmonary fibrosis. Am J Respir Crit Care Med 170: 207‐209, 2004.
 65.Kim SY, Kim HJ, Park MK, Huh JW, Park HY, Ha SY, Shin JH, Lee YS. Mitochondrial E3 ubiquitin protein ligase 1 mediates cigarette smoke‐induced endothelial cell death and dysfunction. Am J Respir Cell Mol Biol 54: 284‐296, 2016.
 66.Korn C, Augustin HG. Mechanisms of vessel pruning and regression. Dev Cell 34: 5‐17, 2015.
 67.Kourembanas S. Exosomes: Vehicles of intercellular signaling, biomarkers, and vectors of cell therapy. Annu Rev Physiol 77: 13‐27, 2015.
 68.Kramann R, Schneider Rebekka K, DiRocco DP, Machado F, Fleig S, Bondzie Philip A, Henderson Joel M, Ebert Benjamin L, Humphreys BD. Perivascular Gli1+ progenitors are key contributors to injury‐induced organ fibrosis. Cell Stem Cell 16: 51‐66.
 69.Kumar ME, Bogard PE, Espinoza FH, Menke DB, Kingsley DM, Krasnow MA. Defining a mesenchymal progenitor niche at single cell resolution. Science 346: 1258810, 2014.
 70.Kurian SM, Fouraschen SMG, Langfelder P, Horvath S, Shaked A, Salomon DR, Olthoff KM. Genomic profiles and predictors of early allograft dysfunction after human liver transplantation. Am J Transplant 15: 1605‐1614, 2015.
 71.Lama VN, Smith L, Badri L, Flint A, Andrei A‐C, Murray S, Wang Z, Liao H, Toews GB, Krebsbach PH, Peters‐Golden M, Pinsky DJ, Martinez FJ, Thannickal VJ. Evidence for tissue‐resident mesenchymal stem cells in human adult lung from studies of transplanted allografts. J Clin Invest 117: 989‐996, 2007.
 72.Lee BC, Kim HS, Shin TH, Kang I, Lee JY, Kim JJ, Kang HK, Seo Y, Lee S, Yu KR, Choi SW, Kang KS. PGE2 maintains self‐renewal of human adult stem cells via EP2‐mediated autocrine signaling and its production is regulated by cell‐to‐cell contact. Sci Rep 6: 26298, 2016.
 73.Lee C, Mitsialis SA, Aslam M, Vitali SH, Vergadi E, Konstantinou G, Sdrimas K, Fernandez‐Gonzalez A, Kourembanas S. Exosomes mediate the cytoprotective action of mesenchymal stromal cells on hypoxia‐induced pulmonary hypertension. Circulation 126: 2601‐2611, 2012.
 74.Lee JW, Fang X, Gupta N, Serikov V, Matthay MA. Allogeneic human mesenchymal stem cells for treatment of E. coli endotoxin‐induced acute lung injury in the ex vivo perfused human lung. Proc Natl Acad Sci U S A 106: 16357‐16362, 2009.
 75.Li C, Li M, Li S, Xing Y, Yang C‐Y, Li A, Borok Z, De Langhe S, Minoo P. Progenitors of secondary crest myofibroblasts are developmentally committed in early lung mesoderm. Stem Cells 33: 999‐1012, 2015.
 76.Li TS, Takahashi M, Ohshima M, Qin SL, Kubo M, Muramatsu K, Hamano K. Myocardial repair achieved by the intramyocardial implantation of adult cardiomyocytes in combination with bone marrow cells. Cell Transplant 17: 695‐703, 2008.
 77.Li X, Zhang Y, Yeung SC, Liang Y, Liang X, Ding Y, Ip MS, Tse HF, Mak JC, Lian Q. Mitochondrial transfer of induced pluripotent stem cell‐derived mesenchymal stem cells to airway epithelial cells attenuates cigarette smoke‐induced damage. Am J Respir Cell Mol Biol 51: 455‐465, 2014.
 78.Liang OD, Mitsialis SA, Chang MS, Vergadi E, Lee C, Aslam M, Fernandez‐Gonzalez A, Liu X, Baveja R, Kourembanas S. Mesenchymal stromal cells expressing heme oxygenase‐1 reverse pulmonary hypertension. Stem Cells 29: 99‐107, 2011.
 79.Lin S‐L, Kisseleva T, Brenner DA, Duffield JS. Pericytes and perivascular fibroblasts are the primary source of collagen‐producing cells in obstructive fibrosis of the kidney. Am J Pathol 173: 1617‐1627, 2008.
 80.Liu R, Bauer AJ, Martin KA. A new editor of smooth muscle phenotype. Circ Res 119: 401‐403, 2016.
 81.Maertens L, Erpicum C, Detry B, Blacher S, Lenoir B, Carnet O, Péqueux C, Cataldo D, Lecomte J, Paupert J, Noel A. Bone marrow‐derived mesenchymal stem cells drive lymphangiogenesis. PLoS One 9: e106976, 2014.
 82.Mancuso MR, Davis R, Norberg SM, O'Brien S, Sennino B, Nakahara T, Yao VJ, Inai T, Brooks P, Freimark B, Shalinsky DR, Hu‐Lowe DD, McDonald DM. Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J Clin Investig 116: 2610‐2621, 2006.
 83.Mangi AA, Noiseux N, Kong D, He H, Rezvani M, Ingwall JS, Dzau VJ. Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts. Nat Med 9: 1195‐1201, 2003.
 84.Marquez‐Curtis LA, Janowska‐Wieczorek A. Enhancing the migration ability of mesenchymal stromal cells by targeting the SDF‐1/CXCR4 axis. Biomed Res Int 2013: 561098, 2013.
 85.Marriott S, Baskir RS, Gaskill C, Menon S, Carrier EJ, Williams J, Talati M, Helm K, Alford CE, Kropski JA, Loyd J, Wheeler L, Johnson J, Austin E, Nozik‐Grayck E, Meyrick B, West JD, Klemm DJ, Majka SM. ABCG2(pos) lung mesenchymal stem cells are a novel pericyte subpopulation that contributes to fibrotic remodeling. Am J Physiol Cell Physiol 307: C684‐C698, 2014.
 86.Marttila‐Ichihara F, Elima K, Auvinen K, Veres TZ, Rantakari P, Weston C, Miyasaka M, Adams D, Jalkanen S, Salmi M. Amine oxidase activity regulates the development of pulmonary fibrosis. FASEB J 31: 2477‐2491, 2017.
 87.McQualter JL, Brouard N, Williams B, Baird BN, Sims‐Lucas S, Yuen K, Nilsson SK, Simmons PJ, Bertoncello I. Endogenous fibroblastic progenitor cells in the adult mouse lung are highly enriched in the Sca‐1 positive cell fraction. Stem Cells 27: 623‐633, 2009.
 88.Mehrad B, Burdick MD, Strieter RM. Fibrocyte CXCR4 regulation as a therapeutic target in pulmonary fibrosis. Int J Biochem Cell Biol 41: 1708‐1718, 2009.
 89.Mendelson A, Frenette PS. Hematopoietic stem cell niche maintenance during homeostasis and regeneration. Nat Med 20: 833‐846, 2014.
 90.Mendez JJ, Ghaedi M, Sivarapatna A, Dimitrievska S, Shao Z, Osuji C, Steinbacher DM, Leffell DJ, Niklason LE. Mesenchymal stromal cells form vascular tubes when placed in fibrin sealant and accelerate wound healing in vivo. Biomaterials 40: 61‐71, 2015.
 91.Méndez‐Ferrer S, Michurina TV, Ferraro F, Mazloom AR, Macarthur BD, Lira SA, Scadden DT, Ma'ayan A, Enikolopov GN, Frenette PS. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466: 829‐834, 2010.
 92.Mofarrahi M, Sigala I, Vassilokopoulos T, Harel S, Guo Y, Debigare R, Maltais F, Hussain SNA. Angiogenesis‐related factors in skeletal muscles of COPD patients: Roles of angiopoietin‐2. J Appl Physiol 114: 1309‐1318, 2013.
 93.Morrison TJ, Jackson MV, Cunningham EK, Kissenpfennig A, McAuley DF, O'Kane CM, Krasnodembskaya AD. Mesenchymal stromal cells modulate macrophages in clinically relevant lung injury models by extracellular vesicle mitochondrial transfer. Am J Respir Crit Care Med 196: 1275‐1286, 2017.
 94.Nabhan A, Brownfield DG, Harbury PB, Krasnow MA, Desai TJ. Single‐cell Wnt signaling niches maintain stemness of alveolar type 2 cells. Science 2018.
 95.Nagy JA, Benjamin L, Zeng H, Dvorak AM, Dvorak HF. Vascular permeability, vascular hyperpermeability and angiogenesis. Angiogenesis 11: 109‐119, 2008.
 96.Nehls V, Denzer K, Drenckhahn D. Pericyte involvement in capillary sprouting during angiogenesis in situ. Cell Tissue Res 270: 469‐474, 1992.
 97.Nemoto S, Takeda K, Yu ZX, Ferrans VJ, Finkel T. Role for mitochondrial oxidants as regulators of cellular metabolism. Mol Cell Biol 20: 7311‐7318, 2000.
 98.Nicolls MR, Hsu JL, Jiang X. Microvascular injury after lung transplantation. Curr Opin Organ Transplant 21: 279‐284, 2016.
 99.Noble PW, Barkauskas CE, Jiang D. Pulmonary fibrosis: Patterns and perpetrators. J Clin Invest 122: 2756‐2762, 2012.
 100.Okamoto R, Yajima T, Yamazaki M, Kanai T, Mukai M, Okamoto S, Ikeda Y, Hibi T, Inazawa J, Watanabe M. Damaged epithelia regenerated by bone marrow‐derived cells in the human gastrointestinal tract. Nat Med 8: 1011‐1017, 2002.
 101.Ortiz LA, DuTreil M, Fattman C, Pandey AC, Torres G, Go K, Phinney DG. Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury. Proc Natl Acad Sci U S A 104: 11002‐11007, 2007.
 102.Ortiz LA, Gambelli F, McBride C, Gaupp D, Baddoo M, Kaminski N, Phinney DG. Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc Natl Acad Sci U S A 100: 8407‐8411, 2003.
 103.Owens GK, Kumar MS, Wamhoff BR. Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol Rev 84: 767‐801, 2004.
 104.Ozerdem U, Stallcup WB. Early contribution of pericytes to angiogenic sprouting and tube formation. Angiogenesis 6: 241‐249, 2003.
 105.Phan SH. Biology of fibroblasts and myofibroblasts. Proc Am Thorac Soc 5: 334‐337, 2008.
 106.Phillips RJ, Burdick MD, Hong K, Lutz MA, Murray LA, Xue YY, Belperio JA, Keane MP, Strieter RM. Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis. J Clin Invest 114: 438‐446, 2004.
 107.Phinney DG. Biochemical heterogeneity of mesenchymal stem cell populations: Clues to their therapeutic efficacy. Cell Cycle 6: 2884‐2889, 2007.
 108.Pizurki L, Zhou Z, Glynos K, Roussos C, Papapetropoulos A. Angiopoietin‐1 inhibits endothelial permeability, neutrophil adherence and IL‐8 production. Br J Pharmacol 139: 329‐336, 2003.
 109.Potter DR, Miyazawa BY, Gibb SL, Deng X, Togaratti PP, Croze RH, Srivastava AK, Trivedi A, Matthay M, Holcomb JB, Schreiber MA, Pati S. Mesenchymal stem cell‐derived extracellular vesicles attenuate pulmonary vascular permeability and lung injury induced by hemorrhagic shock and trauma. J Trauma Acute Care Surg 84: 245‐256, 2018.
 110.Price MA, Wanshura LEC, Yang J, Carlson J, Xiang B, Li G, Ferrone S, Dudek AZ, Turley EA, McCarthy JB. CSPG4, a potential therapeutic target, facilitates malignant progression of melanoma. Pigment Cell Melanoma Res 24: 1148‐1157, 2011.
 111.Prockop DJ. Repair of tissues by adult stem/progenitor cells (MSCs): Controversies, myths, and changing paradigms. Mol Ther 17: 939‐946, 2009.
 112.Prockop DJ, Oh JY. Mesenchymal stem/stromal cells (MSCs): Role as guardians of inflammation. Mol Ther 20: 14‐20, 2012.
 113.Qiao L, Nishimura T, Shi L, Sessions D, Thrasher A, Trudell JR, Berry GJ, Pearl RG, Kao PN. Endothelial fate mapping in mice with pulmonary hypertension. Circulation 129: 692‐703, 2014.
 114.Ren S, Johnson BG, Kida Y, Ip C, Davidson KC, Lin S‐L, Kobayashi A, Lang RA, Hadjantonakis A‐K, Moon RT, Duffield JS. LRP‐6 is a coreceptor for multiple fibrogenic signaling pathways in pericytes and myofibroblasts that are inhibited by DKK‐1. Proc Natl Acad Sci U S A 110: 1440‐1445, 2013.
 115.Rensen SSM, Doevendans P, van Eys G. Regulation and characteristics of vascular smooth muscle cell phenotypic diversity. Neth Heart J 15: 100‐108, 2007.
 116.Rock JR, Barkauskas CE, Cronce MJ, Xue Y, Harris JR, Liang J, Noble PW, Hogan BLM. Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition. Proc Natl Acad Sci 108: 1475‐1483, 2011.
 117.Rojas M, Xu J, Woods CR, Mora AL, Spears W, Roman J, Brigham KL. Bone marrow‐derived mesenchymal stem cells in repair of the injured lung. Am J Respir Cell Mol Biol 33: 145‐152, 2005.
 118.Sato K, Ozaki K, Oh I, Meguro A, Hatanaka K, Nagai T, Muroi K, Ozawa K. Nitric oxide plays a critical role in suppression of T‐cell proliferation by mesenchymal stem cells. Blood 109: 228‐234, 2007.
 119.Schafer MJ, White TA, Iijima K, Haak AJ, Ligresti G, Atkinson EJ, Oberg AL, Birch J, Salmonowicz H, Zhu Y, Mazula DL, Brooks RW, Fuhrmann‐Stroissnigg H, Pirtskhalava T, Prakash YS, Tchkonia T, Robbins PD, Aubry MC, Passos JF, Kirkland JL, Tschumperlin DJ, Kita H, LeBrasseur NK. Cellular senescence mediates fibrotic pulmonary disease. Nat Commun 8: 14532, 2017.
 120.Schmidt A, Zhang XM, Joshi RN, Iqbal S, Wahlund C, Gabrielsson S, Harris RA, Tegner J. Human macrophages induce CD4(+)Foxp3(+) regulatory T cells via binding and re‐release of TGF‐beta. Immunol Cell Biol 94: 747‐762, 2016.
 121.Schrimpf C, Teebken OE, Wilhelmi M, Duffield JS. The role of pericyte detachment in vascular rarefaction. J Vasc Res 51: 247‐258, 2014.
 122.Sheikh AQ, Lighthouse JK, Greif DM. Recapitulation of developing artery muscularization in pulmonary hypertension. Cell Rep 6: 809‐817, 2014.
 123.Shenoy V, Qi Y, Katovich MJ, Raizada MK. ACE2, a promising therapeutic target for pulmonary hypertension. Curr Opin Pharmacol 11: 150‐155, 2011.
 124.Shi Y, Su J, Roberts AI, Shou P, Rabson AB, Ren G. How mesenchymal stem cells interact with tissue immune responses. Trends Immunol 33: 136‐143, 2012.
 125.Silva JD, Lopes‐Pacheco M, Paz AHR, Cruz FF, Melo EB, de Oliveira MV, Xisto DG, Capelozzi VL, Morales MM, Pelosi P, Cirne‐Lima E, Rocco PRM. Mesenchymal stem cells from bone marrow, adipose tissue, and lung tissue differentially mitigate lung and distal organ damage in experimental acute respiratory distress syndrome. Crit Care Med 46: e132‐e140, 2018.
 126.Sims DE. Diversity within pericytes. Clin Exp Pharmacol Physiol 27: 842‐846, 2000.
 127.Sims‐Lucas S, Schaefer C, Bushnell D, Ho J, Logar A, Prochownik E, Gittes G, Bates CM. Endothelial progenitors exist within the kidney and lung mesenchyme. PLoS One 8: e65993, 2013.
 128.Sinclair KA, Yerkovich ST, Hopkins PM, Chambers DC. Characterization of intercellular communication and mitochondrial donation by mesenchymal stromal cells derived from the human lung. Stem Cell Res Ther 7: 91, 2016.
 129.Song JS, Kang CM, Kang HH, Yoon HK, Kim YK, Kim KH, Moon HS, Park SH. Inhibitory effect of CXC chemokine receptor 4 antagonist AMD3100 on bleomycin induced murine pulmonary fibrosis. Exp Mol Med 42: 465‐472, 2010.
 130.Song S, Ewald AJ, Stallcup W, Werb Z, Bergers G. PDGFR[beta]+ perivascular progenitor cells in tumours regulate pericyte differentiation and vascular survival. Nat Cell Biol 7: 870‐879, 2005.
 131.Steinhauser ML, Lee RT. Pericyte progenitors at the crossroads between fibrosis and regeneration. Circ Res 112: 230‐232, 2013.
 132.Sullivan AK, Simonian PL, Falta MT, Mitchell JD, Cosgrove GP, Brown KK, Kotzin BL, Voelkel NF, Fontenot AP. Oligoclonal CD4+ T cells in the lungs of patients with severe emphysema. Am J Respir Crit Care Med 172: 590‐596, 2005.
 133.Sun CK, Yen CH, Lin YC, Tsai TH, Chang LT, Kao YH, Chua S, Fu M, Ko SF, Leu S, Yip HK. Autologous transplantation of adipose‐derived mesenchymal stem cells markedly reduced acute ischemia‐reperfusion lung injury in a rodent model. J Transl Med 9: 118, 2011.
 134.Tada Y, Majka S, Carr M, Harral J, Crona D, Kuriyama T, West J. Molecular effects of loss of BMPR2 signaling in smooth muscle in a transgenic mouse model of PAH. Am J Physiol Lung Cell Mol Physiol 292: L1556‐L1563, 2007.
 135.Takeda K, Ning F, Domenico J, Okamoto M, Ashino S, Kim SH, Jeong YY, Shiraishi Y, Terada N, Sutherland ER, Gelfand EW. Activation of p70S6 Kinase‐1 in mesenchymal stem cells is essential to lung tissue repair. Stem Cells Transl Med 7: 551‐558, 2018.
 136.Tao H, Han Z, Han ZC, Li Z. Proangiogenic features of mesenchymal stem cells and their therapeutic applications. Stem Cells Int 2016: 11, 2016.
 137.van Haaften T, Byrne R, Bonnet S, Rochefort GY, Akabutu J, Bouchentouf M, Rey‐Parra GJ, Galipeau J, Haromy A, Eaton F, Chen M, Hashimoto K, Abley D, Korbutt G, Archer SL, Thebaud B. Airway delivery of mesenchymal stem cells prevents arrested alveolar growth in neonatal lung injury in rats. Am J Respir Crit Care Med 180: 1131‐1142, 2009.
 138.Voelkel NF, Douglas IS, Nicolls M. Angiogenesis in chronic lung disease. Chest 131: 874‐879, 2007.
 139.Wang C, de Mochel NSR, Christenson SA, Cassandras M, Moon R, Brumwell AN, Byrnes LE, Li A, Yokosaki Y, Shan P, Sneddon JB, Jablons D, Lee PJ, Matthay MA, Chapman HA, Peng T. Expansion of hedgehog disrupts mesenchymal identity and induces emphysema phenotype. J Clin Invest 128: 4343‐4358, 2018.
 140.Watt SM, Gullo F, van der Garde M, Markeson D, Camicia R, Khoo CP, Zwaginga JJ. The angiogenic properties of mesenchymal stem/stromal cells and their therapeutic potential. Br Med Bull 108: 25‐53, 2013.
 141.West J, Harral J, Lane K, Deng Y, Ickes B, Crona D, Albu S, Stewart D, Fagan K. Mice expressing BMPR2R899X transgene in smooth muscle develop pulmonary vascular lesions. Am J Physiol Lung Cell Mol Physiol 295: L744‐L755, 2008.
 142.West JD, Austin ED, Gaskill C, Marriott S, Baskir R, Bilousova G, Jean J‐C, Hemnes AR, Menon S, Bloodworth NC, Fessel JP, Kropski JA, Irwin D, Ware LB, Wheeler L, Hong CC, Meyrick B, Loyd JE, Bowman AB, Ess KC, Klemm DJ, Young PP, Merryman WD, Kotton D, Majka SM. Identification of a common Wnt‐associated genetic signature across multiple cell types in pulmonary arterial hypertension. Am J Physiol Cell Physiol 307: C415‐C430, 2014.
 143.Wisniewski HG, Vilcek J. TSG‐6: An IL‐1/TNF‐inducible protein with anti‐inflammatory activity. Cytokine Growth Factor Rev 8: 143‐156, 1997.
 144.Xia H, Gilbertsen A, Herrera J, Racila E, Smith K, Peterson M, Griffin T, Benyumov A, Yang L, Bitterman PB, Henke CA. Calcium‐binding protein S100A4 confers mesenchymal progenitor cell fibrogenicity in idiopathic pulmonary fibrosis. J Clin Invest 127: 2586‐2597, 2017.
 145.Xie T, Liang J, Liu N, Huan C, Zhang Y, Liu W, Kumar M, Xiao R, DArmiento J, Metzger D, Chambon P, Papaioannou VE, Stripp BR, Jiang D, Noble PW. Transcription factor TBX4 regulates myofibroblast accumulation and lung fibrosis. J Clin Invest 126: 3063‐3079, 2016.
 146.Xie T, Wang Y, Deng N, Huang G, Taghavifar F, Geng Y, Liu N, Kulur V, Yao C, Chen P, Liu Z, Stripp B, Tang J, Liang J, Noble PW, Jiang D. Single‐cell deconvolution of fibroblast heterogeneity in mouse pulmonary fibrosis. Cell Rep 22: 3625‐3640, 2018.
 147.Xu J, Gonzalez ET, Iyer SS, Mac V, Mora AL, Sutliff RL, Reed A, Brigham KL, Kelly P, Rojas M. Use of senescence‐accelerated mouse model in bleomycin‐induced lung injury suggests that bone marrow‐derived cells can alter the outcome of lung injury in aged mice. J Gerontol A Biol Sci Med Sci 64A: 731‐739, 2009.
 148.Xu J, Mora A, Shim H, Stecenko A, Brigham KL, Rojas M. Role of the SDF‐1/CXCR4 axis in the pathogenesis of lung injury and fibrosis. Am J Respir Cell Mol Biol 37: 291‐299, 2007.
 149.Xu J, Qu J, Cao L, Sai Y, Chen C, He L, Yu L. Mesenchymal stem cell‐based angiopoietin‐1 gene therapy for acute lung injury induced by lipopolysaccharide in mice. J Pathol 214: 472‐481, 2008.
 150.Yagi H, Soto‐Gutierrez A, Navarro‐Alvarez N, Nahmias Y, Goldwasser Y, Kitagawa Y, Tilles AW, Tompkins RG, Parekkadan B, Yarmush ML. Reactive bone marrow stromal cells attenuate systemic inflammation via sTNFR1. Mol Ther 18: 1857‐1864, 2010.
 151.Yi ES, Salgado M, Williams S, Kim SJ, Masliah E, Yin S, Ulich TR. Keratinocyte growth factor decreases pulmonary edema, transforming growth factor‐beta and platelet‐derived growth factor‐BB expression, and alveolar type II cell loss in bleomycin‐induced lung injury. Inflammation 22: 315‐325, 1998.
 152.Yu Q, Chan SY. Mitochondrial and metabolic drivers of pulmonary vascular endothelial dysfunction in pulmonary hypertension. Adv Exp Med Biol 967: 373‐383, 2017.
 153.Zepp JA, Zacharias WJ, Frank DB, Cavanaugh CA, Zhou S, Morley MP, Morrisey EE. Distinct mesenchymal lineages and niches promote epithelial self‐renewal and myofibrogenesis in the lung. Cell 170: 1134‐1148.e1110, 2017.
 154.Zhang J, Patel JM. Role of the CX3CL1‐CX3CR1 axis in chronic inflammatory lung diseases. Int J Clin Exp Med 3: 233‐244, 2010.


Teaching Material

S. M. Majka, M. Rojas, I. Petrache, R. F. Foronjy. Mesenchymal Regulation of the Microvascular Niche in Chronic Lung Diseases. Compr Physiol 9: 2019, 1431-1441.

Didactic Synopsis

Major Teaching Points:

  • Understand the importance of bone-marrow-derived and resident lung mesenchymal progenitors (MPCs) in the pulmonary vasculature during tissue homeostasis and disease states.
  • Much of our understanding of lung MPCs is from studies performed using bone-marrow MPCs (BM-MPCs) as a therapeutic to ameliorate lung injury or disease. However, recent studies and novel models currently allow the study of resident lung MPCs.
  • MPCs are intimately associated with the microvasculature in both BM and lung tissues.

-MPCs express markers common to both vascular smooth muscle and pericytes.

-However, the role MPCs play in terms of microvascular regulation is less clear at this time.

  • Age and senescence of MPCs influence inflammation and the severity of lung injury in murine models.

Didactic Legends

The following legends to the figures that appear throughout the article are written to be useful for teaching.

Figure 1 Teaching points: During pulmonary tissue homeostasis, cells that comprise the microvascular niche are intimately associated and include microvascular endothelial cells (MVECs, pink), pericyte/vascular smooth muscle cells (vSMCs, red), mesenchymal progenitor cells (MPCs, green), fibroblasts (FB, purple), and alveolar epithelial cells (AECs, yellow). Dysfunction in one or more of these cell types, here specifically MPCs, impacts vascular homeostasis and remodeling. Following injury or during disease remodeling is also complex and may be described as (1) involving MVEC, SMC, or fibroblast proliferation; (2) loss of differentiated SMC phenotypes with mesenchymal proliferation; and /or (3) loss of microvessel structures or rarefaction. Additional components of the niche, which may influence these processes, are immune cells, such as T-cells and macrophages.

Figure 2 Teaching points: When making a comparison between mesenchymal progenitor cells (MPCs), fibroblasts, and pericytes, there is a significant overlap in cell surface marker expression; however, the phenotypes differ in their contractile profiles/function as well as the ability to form clonal colonies (CFU-F).

Figure 3 Teaching points: Primary MPCs isolated from PAH, COPD, and IPF patient lung tissue explants exhibit common transcriptional signatures of deregulated Wnt signaling, which affects both microvascular barrier function and angiogenesis.


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How to Cite

Susan M. Majka, Mauricio Rojas, Irina Petrache, Robert F. Foronjy. Mesenchymal Regulation of the Microvascular Niche in Chronic Lung Diseases. Compr Physiol 2019, 9: 1431-1441. doi: 10.1002/cphy.c180043