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Pericytes in the Lung

  • Chi F. Hung
  • Carole L. Wilson
  • Lynn M. SchnappEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1122)

Abstract

The lung has numerous roles, including gas exchange, immune surveillance, and barrier function. Being a highly vascularized organ, the lung receives dual blood supply from both the pulmonary and bronchial circulation. Therefore, pericytes likely play a prominent role in lung physiology given their localization in the perivascular niche. New genetic approaches have increased our understanding of the origin and the diverse functions of lung pericytes. Lung pericytes are myofibroblast progenitors, contributing to development of fibrosis in mouse models. Lung pericytes are also capable of responding to danger signals and amplify the inflammatory response through elaboration of cytokines and adhesion molecules. In this chapter, we describe the molecular, anatomical, and phenotypical characterization of lung pericytes. We further highlight their potential roles in the pathogenesis of lung diseases including pulmonary fibrosis, asthma, and pulmonary hypertension. Finally, current gaps in knowledge and areas of ongoing investigation in lung pericyte biology are also discussed.

Keywords

Lung pericytes PDGFRβ Lung development Lung myofibroblasts Pulmonary fibrosis Lung injury Lung inflammation 

Notes

Acknowledgments

The authors thank all the members of the Schnapp and Hung laboratories who have contributed to studies described in this chapter. We also thank Seth Bollenbecker for providing the artwork in Fig. 3.3.

References

  1. Akamatsu T, Arai Y, Kosugi I, Kawasaki H, Meguro S, Sakao M, Shibata K, Suda T, Chida K, Iwashita T (2013) Direct isolation of myofibroblasts and fibroblasts from bleomycin-injured lungs reveals their functional similarities and differences. Fibrogenesis Tissue Repair 6(1):15. https://doi.org/10.1186/1755-1536-6-15. PubMed PMID: 23927729; PMCID: PMC3751789CrossRefPubMedPubMedCentralGoogle Scholar
  2. Armulik A, Genove G, Betsholtz C (2011) Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev Cell 21(2):193–215. https://doi.org/10.1016/j.devcel.2011.07.001. PubMed PMID: 21839917CrossRefPubMedGoogle Scholar
  3. Bagley RG, Weber W, Rouleau C, Teicher BA (2005) Pericytes and endothelial precursor cells: cellular interactions and contributions to malignancy. Cancer Res 65(21):9741–9750. https://doi.org/10.1158/0008-5472.CAN-04-4337. PubMed PMID: 16266995CrossRefPubMedGoogle Scholar
  4. Bagley RG, Rouleau C, Morgenbesser SD, Weber W, Cook BP, Shankara S, Madden SL, Teicher BA (2006) Pericytes from human non-small cell lung carcinomas: an attractive target for anti-angiogenic therapy. Microvasc Res 71(3):163–174. https://doi.org/10.1016/j.mvr.2006.03.002. Epub 2006/04/19. PubMed PMID: 16624341CrossRefPubMedGoogle Scholar
  5. Bardin N, Anfosso F, Masse JM, Cramer E, Sabatier F, Le Bivic A, Sampol J, Dignat-George F (2001) Identification of CD146 as a component of the endothelial junction involved in the control of cell-cell cohesion. Blood 98(13):3677–3684. PubMed PMID: 11739172CrossRefGoogle Scholar
  6. Barkauskas CE, Cronce MJ, Rackley CR, Bowie EJ, Keene DR, Stripp BR, Randell SH, Noble PW, Hogan BL (2013) Type 2 alveolar cells are stem cells in adult lung. J Clin Invest 123(7):3025–3036. https://doi.org/10.1172/JCI68782. Epub 2013/08/08. PubMed PMID: 23921127; PMCID: PMC3696553CrossRefPubMedPubMedCentralGoogle Scholar
  7. Bichsel CA, Hall SR, Schmid RA, Guenat OT, Geiser T (2015) Primary human lung pericytes support and stabilize in vitro perfusable microvessels. Tissue Eng Part A 21(15–16):2166–2176. https://doi.org/10.1089/ten.TEA.2014.0545. PubMed PMID: 25891384CrossRefPubMedGoogle Scholar
  8. Chow K, Fessel JP, Kaoriihida S, Schmidt EP, Gaskill C, Alvarez D, Graham B, Harrison DG, Wagner DH Jr, Nozik-Grayck E, West JD, Klemm DJ, Majka SM (2013) Dysfunctional resident lung mesenchymal stem cells contribute to pulmonary microvascular remodeling. Pulm Circ 3(1):31–49. https://doi.org/10.4103/2045-8932.109912. PubMed PMID: 23662173; PMCID: PMC3641738CrossRefPubMedPubMedCentralGoogle Scholar
  9. Crisan M, Yap S, Casteilla L, Chen CW, Corselli M, Park TS, Andriolo G, Sun B, Zheng B, Zhang L, Norotte C, Teng PN, Traas J, Schugar R, Deasy BM, Badylak S, Buhring HJ, Giacobino JP, Lazzari L, Huard J, Peault B (2008) A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 3(3):301–313. https://doi.org/10.1016/j.stem.2008.07.003. PubMed PMID: 18786417CrossRefPubMedGoogle Scholar
  10. Epling GP (1966) Electron microscopic observations of pericytes of small blood vessels in the lungs and hearts of normal cattle and swine. Anat Rec 155:513–530CrossRefGoogle Scholar
  11. 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 (2017) Disruption of lineage specification in adult pulmonary mesenchymal progenitor cells promotes microvascular dysfunction. J Clin Invest 127(6):2262–2276. https://doi.org/10.1172/JCI88629. Epub 2017/05/04. PubMed PMID: 28463231; PMCID: PMC5451236CrossRefPubMedPubMedCentralGoogle Scholar
  12. 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 (2017) Pericytes of multiple organs do not behave as mesenchymal stem cells in vivo. Cell Stem Cell 20(3):345–359.e5. https://doi.org/10.1016/j.stem.2016.12.006. PubMed PMID: 28111199; PMCID: PMC5337131CrossRefPubMedPubMedCentralGoogle Scholar
  13. Gushi A, Tanaka M, Tsuyama S, Nagai T, Kanzaki T, Kanekura T, Matsuyama T (2008) The 3G5 antigen is expressed in dermal mast cells but not pericytes. J Cutan Pathol 35(3):278–284. https://doi.org/10.1111/j.1600-0560.2007.00809.x. PubMed PMID: 18251741CrossRefPubMedGoogle Scholar
  14. Hellstrom M, Kalen M, Lindahl P, Abramsson A, Betsholtz C (1999) Role of PDGF-B and PDGFR-beta in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development 126(14):3047–3055. PubMed PMID: 10375497PubMedGoogle Scholar
  15. Helmbold P, Nayak RC, Marsch WC, Herman IM (2001a) Isolation and in vitro characterization of human dermal microvascular pericytes. Microvasc Res 61(2):160–165. https://doi.org/10.1006/mvre.2000.2292. PubMed PMID: 11254395CrossRefPubMedGoogle Scholar
  16. Helmbold P, Wohlrab J, Marsch WC, Nayak RC (2001b) Human dermal pericytes express 3G5 ganglioside—a new approach for microvessel histology in the skin. J Cutan Pathol 28(4):206–210. PubMed PMID: 11426828CrossRefGoogle Scholar
  17. Hemnes AR, Humbert M (2017) Pathobiology of pulmonary arterial hypertension: understanding the roads less travelled. Eur Respir Rev 26(146). https://doi.org/10.1183/16000617.0093-2017
  18. Henderson NC, Arnold TD, Katamura Y, Giacomini MM, Rodriguez JD, McCarty JH, Pellicoro A, Raschperger E, Betsholtz C, Ruminski PG, Griggs DW, Prinsen MJ, Maher JJ, Iredale JP, Lacy-Hulbert A, Adams RH, Sheppard D (2013) Targeting of alphav integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat Med 19(12):1617–1624. https://doi.org/10.1038/nm.3282. PubMed PMID: 24216753; PMCID: PMC3855865CrossRefPubMedGoogle Scholar
  19. Humphreys BD, Lin SL, Kobayashi A, Hudson TE, Nowlin BT, Bonventre JV, Valerius MT, McMahon AP, Duffield JS (2010) Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. Am J Pathol 176(1):85–97. https://doi.org/10.2353/ajpath.2010.090517. PubMed PMID: 20008127; PMCID: PMC2797872CrossRefPubMedPubMedCentralGoogle Scholar
  20. Hung C, Linn G, Chow YH, Kobayashi A, Mittelsteadt K, Altemeier WA, Gharib SA, Schnapp LM, Duffield JS (2013) Role of lung pericytes and resident fibroblasts in the pathogenesis of pulmonary fibrosis. Am J Respir Crit Care Med 188(7):820–830. https://doi.org/10.1164/rccm.201212-2297OC. PubMed PMID: 23924232; PMCID: 3826269CrossRefPubMedPubMedCentralGoogle Scholar
  21. Hung CF, Mittelsteadt KL, Brauer R, McKinney BL, Hallstrand TS, Parks WC, Chen P, Schnapp LM, Liles WC, Duffield JS, Altemeier WA (2017a) Lung pericyte-like cells are functional interstitial immune sentinel cells. Am J Physiol Lung Cell Mol Physiol 312(4):L556–L567. https://doi.org/10.1152/ajplung.00349.2016. PubMed PMID: 28188224; PMCID: PMC5407093CrossRefPubMedPubMedCentralGoogle Scholar
  22. Hung CF, Chow YH, Liles WC, Altemeier WA, Schnapp LM (2017b) Ablation of Pericyte-like cells in lungs by oropharyngeal aspiration of diphtheria toxin. Am J Respir Cell Mol Biol 56(2):160–167. https://doi.org/10.1165/rcmb.2016-0083MA. PubMed PMID: 27779900CrossRefPubMedPubMedCentralGoogle Scholar
  23. Hung CF, Wilson CL, Chow YH, Schnapp LM (2018) Role of integrin alpha8 in murine model of lung fibrosis. PLoS One 13(5):e0197937. https://doi.org/10.1371/journal.pone.0197937. Epub 2018/05/29. PubMed PMID: 29813125CrossRefPubMedPubMedCentralGoogle Scholar
  24. Jansson D, Rustenhoven J, Feng S, Hurley D, Oldfield RL, Bergin PS, Mee EW, Faull RL, Dragunow M (2014) A role for human brain pericytes in neuroinflammation. J Neuroinflammation 11:104. https://doi.org/10.1186/1742-2094-11-104. PubMed PMID: 24920309; PMCID: PMC4105169CrossRefPubMedPubMedCentralGoogle Scholar
  25. Johnson JR, Folestad E, Rowley JE, Noll EM, Walker SA, Lloyd CM, Rankin SM, Pietras K, Eriksson U, Fuxe J (2015) Pericytes contribute to airway remodeling in a mouse model of chronic allergic asthma. Am J Physiol Lung Cell Mol Physiol 308(7):L658–L671. https://doi.org/10.1152/ajplung.00286.2014. Epub 2015/02/01. PubMed PMID: 25637607; PMCID: PMC4385988CrossRefPubMedPubMedCentralGoogle Scholar
  26. 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, Jr., 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 2011;29(4):725–735. doi: https://doi.org/10.1002/stem.604. Epub 2011/02/12. PubMed PMID: 21312316; PMCID: PMC3322548
  27. Kato K, Dieguez-Hurtado R, Park DY, Hong SP, Kato-Azuma S, Adams S, Stehling M, Trappmann B, Wrana JL, Koh GY, Adams RH (2018) Pulmonary pericytes regulate lung morphogenesis. Nat Commun 9(1):2448. https://doi.org/10.1038/s41467-018-04913-2. PubMed PMID: 29934496; PMCID: PMC6015030CrossRefPubMedPubMedCentralGoogle Scholar
  28. Kerr BA, West XZ, Kim YW, Zhao Y, Tischenko M, Cull RM, Phares TW, Peng XD, Bernier-Latmani J, Petrova TV, Adams RH, Hay N, Naga Prasad SV, Byzova TV (2016) Stability and function of adult vasculature is sustained by Akt/Jagged1 signalling axis in endothelium. Nat Commun 7:10960. https://doi.org/10.1038/ncomms10960. Epub 2016/03/15. PubMed PMID: 26971877; PMCID: PMC4793084CrossRefPubMedPubMedCentralGoogle Scholar
  29. Kramann R, Schneider RK, DiRocco DP, Machado F, Fleig S, Bondzie PA, Henderson JM, Ebert BL, Humphreys BD (2015) Perivascular Gli1+ progenitors are key contributors to injury-induced organ fibrosis. Cell Stem Cell 16(1):51–66. https://doi.org/10.1016/j.stem.2014.11.004. PubMed PMID: 25465115; PMCID: PMC4289444CrossRefPubMedGoogle Scholar
  30. Lin SL, Kisseleva T, Brenner DA, Duffield JS (2008) Pericytes and perivascular fibroblasts are the primary source of collagen-producing cells in obstructive fibrosis of the kidney. Am J Pathol 173(6):1617–1627. https://doi.org/10.2353/ajpath.2008.080433. ajpath.2008.080433 [pii]. Epub 2008/11/15. PubMed PMID: 19008372; PMCID: 2626374CrossRefPubMedPubMedCentralGoogle Scholar
  31. 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 (2014) ABCG2pos lung mesenchymal stem cells are a novel pericyte subpopulation that contributes to fibrotic remodeling. Am J Physiol Cell Physiol 307(8):C684–C698. https://doi.org/10.1152/ajpcell.00114.2014. PubMed PMID: 25122876; PMCID: PMC4200000CrossRefPubMedPubMedCentralGoogle Scholar
  32. McAllister KA, Grogg KM, Johnson DW, Gallione CJ, Baldwin MA, Jackson CE, Helmbold EA, Markel DS, McKinnon WC, Murrell J et al (1994) Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet 8(4):345–351. https://doi.org/10.1038/ng1294-345. PubMed PMID: 7894484CrossRefPubMedGoogle Scholar
  33. Mederacke I, Hsu CC, Troeger JS, Huebener P, Mu X, Dapito DH, Pradere JP, Schwabe RF (2013) Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat Commun 4:2823. https://doi.org/10.1038/ncomms3823. Epub 2013/11/23. PubMed PMID: 24264436; PMCID: PMC4059406CrossRefPubMedPubMedCentralGoogle Scholar
  34. Murfee WL, Skalak TC, Peirce SM (2005) Differential arterial/venous expression of NG2 proteoglycan in perivascular cells along microvessels: identifying a venule-specific phenotype. Microcirculation 12(2):151–160. https://doi.org/10.1080/10739680590904955. PubMed PMID: 15824037CrossRefPubMedGoogle Scholar
  35. Murfee WL, Rehorn MR, Peirce SM, Skalak TC (2006) Perivascular cells along venules upregulate NG2 expression during microvascular remodeling. Microcirculation 13(3):261–273. https://doi.org/10.1080/10739680600559153. PubMed PMID: 16627368CrossRefPubMedGoogle Scholar
  36. Nehls V, Drenckhahn D (1991) Heterogeneity of microvascular pericytes for smooth muscle type alpha-actin. J Cell Biol 113(1):147–154. PubMed PMID: 2007619; PMCID: PMC2288926CrossRefGoogle Scholar
  37. Ogura S, Kurata K, Hattori Y, Takase H, Ishiguro-Oonuma T, Hwang Y, Ahn S, Park I, Ikeda W, Kusuhara S, Fukushima Y, Nara H, Sakai H, Fujiwara T, Matsushita J, Ema M, Hirashima M, Minami T, Shibuya M, Takakura N, Kim P, Miyata T, Ogura Y, Uemura A (2017) Sustained inflammation after pericyte depletion induces irreversible blood-retina barrier breakdown. JCI Insight 2(3):e90905. https://doi.org/10.1172/jci.insight.90905. Epub 2017/02/15. PubMed PMID: 28194443; PMCID: PMC5291729 employees of Astellas Pharma Inc.CrossRefPubMedPubMedCentralGoogle Scholar
  38. Patel MS, Taylor GP, Bharya S, Al-Sanna'a N, Adatia I, Chitayat D, Lewis MES, Human DG (2004) Abnormal pericyte recruitment as a cause for pulmonary hypertension in Adams–Oliver syndrome. Am J Med Genet A 129A(3):294–299. https://doi.org/10.1002/ajmg.a.30221CrossRefPubMedGoogle Scholar
  39. Peng T, Tian Y, Boogerd CJ, Lu MM, Kadzik RS, Stewart KM, Evans SM, Morrisey EE (2013) Coordination of heart and lung co-development by a multipotent cardiopulmonary progenitor. Nature 500(7464):589–592. https://doi.org/10.1038/nature12358. PubMed PMID: 23873040; PMCID: PMC3758448CrossRefPubMedPubMedCentralGoogle Scholar
  40. Que J, Wilm B, Hasegawa H, Wang F, Bader D, Hogan BL (2008) Mesothelium contributes to vascular smooth muscle and mesenchyme during lung development. Proc Natl Acad Sci U S A 105(43):16626–16630. https://doi.org/10.1073/pnas.0808649105. PubMed PMID: 18922767; PMCID: PMC2567908CrossRefPubMedPubMedCentralGoogle Scholar
  41. Ricard N, Tu L, Le Hiress M, Huertas A, Phan C, Thuillet R, Sattler C, Fadel E, Seferian A, Montani D, Dorfmuller P, Humbert M, Guignabert C (2014) Increased pericyte coverage mediated by endothelial-derived fibroblast growth factor-2 and interleukin-6 is a source of smooth muscle-like cells in pulmonary hypertension. Circulation 129(15):1586–1597. https://doi.org/10.1161/CIRCULATIONAHA.113.007469. PubMed PMID: 24481949CrossRefPubMedGoogle Scholar
  42. Rock JR, Barkauskas CE, Cronce MJ, Xue Y, Harris JR, Liang J, Noble PW, Hogan BL (2011) Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition. Proc Natl Acad Sci U S A 108(52):E1475–E1483. https://doi.org/10.1073/pnas.1117988108. PubMed PMID: 22123957; PMCID: PMC3248478CrossRefPubMedPubMedCentralGoogle Scholar
  43. Rustenhoven J, Jansson D, Smyth LC, Dragunow M (2017) Brain pericytes as mediators of neuroinflammation. Trends Pharmacol Sci 38(3):291–304. https://doi.org/10.1016/j.tips.2016.12.001. Epub 2016/12/27. PubMed PMID: 28017362CrossRefPubMedGoogle Scholar
  44. Sava P, Ramanathan A, Dobronyi A, Peng X, Sun H, Ledesma-Mendoza A, Herzog EL, Gonzalez AL (2017) Human pericytes adopt myofibroblast properties in the microenvironment of the IPF lung. JCI Insight. 2(24). https://doi.org/10.1172/jci.insight.96352. PubMed PMID: 29263297; PMCID: PMC5752282
  45. Shepro D, Morel NM (1993) Pericyte physiology. FASEB J 7(11):1031–1038. PubMed PMID: 8370472CrossRefGoogle Scholar
  46. Sims DE, Westfall JA (1983) Analysis of relationships between pericytes and gas exchange capillaries in neonatal and mature bovine lungs. Microvasc Res 25(3):333–342. PubMed PMID: 6855632CrossRefGoogle Scholar
  47. Sims-Lucas S, Schaefer C, Bushnell D, Ho J, Logar A, Prochownik E, Gittes G, Bates CM (2013) Endothelial progenitors exist within the kidney and lung mesenchyme. PLoS One 8(6):e65993. https://doi.org/10.1371/journal.pone.0065993. PubMed PMID: 23823180; PMCID: PMC3688860CrossRefPubMedPubMedCentralGoogle Scholar
  48. Thalgott J, Lebrin F (2015) Pericytes as targets in hereditary hemorrhagic telangiectasia. Front Genet 6:37CrossRefGoogle Scholar
  49. Valdez CN, Arboleda-Velasquez JF, Amarnani DS, Kim LA, D'Amore PA (2014) Retinal microangiopathy in a mouse model of inducible mural cell loss. Am J Pathol 184(10):2618–2626. https://doi.org/10.1016/j.ajpath.2014.06.011. S0002-9440(14)00366-6 [pii]. Epub 2014/08/06. PubMed PMID: 25092275CrossRefPubMedPubMedCentralGoogle Scholar
  50. von Tell D, Armulik A, Betsholtz C (2006) Pericytes and vascular stability. Exp Cell Res 312(5):623–629. https://doi.org/10.1016/j.yexcr.2005.10.019. PubMed PMID: 16303125CrossRefGoogle Scholar
  51. Weibel ER (1974) On pericytes, particularly their existence on lung capillaries. Microvasc Res 8(2):218–235. PubMed PMID: 4140459CrossRefGoogle Scholar
  52. Wilson CL, Stephenson SE, Higuero JP, Feghali-Bostwick C, Hung CF, Schnapp LM (2018) Characterization of human PDGFRβ-positive pericytes from IPF and non-IPF lungs. Am J Physiol Lung Cell Mol Physiol. https://doi.org/10.1152/ajplung.00289.2018
  53. Yata Y, Scanga A, Gillan A, Yang L, Reif S, Breindl M, Brenner DA, Rippe RA (2003) DNase I-hypersensitive sites enhance alpha1(I) collagen gene expression in hepatic stellate cells. Hepatology 37(2):267–276. https://doi.org/10.1053/jhep.2003.50067. PubMed PMID: 12540776CrossRefPubMedGoogle Scholar
  54. Yuan K, Orcholski ME, Panaroni C, Shuffle EM, Huang NF, Jiang X, Tian W, Vladar EK, Wang L, Nicolls MR, Wu JY, de Jesus Perez VA (2015) Activation of the Wnt/planar cell polarity pathway is required for pericyte recruitment during pulmonary angiogenesis. Am J Pathol 185(1):69–84. https://doi.org/10.1016/j.ajpath.2014.09.013. PubMed PMID: 25447046; PMCID: PMC4278244CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Chi F. Hung
    • 1
  • Carole L. Wilson
    • 2
  • Lynn M. Schnapp
    • 2
    Email author
  1. 1.Division of Pulmonary, Critical Care and Sleep MedicineUniversity of WashingtonSeattleUSA
  2. 2.Division of Pulmonary, Critical Care, Allergy and Sleep MedicineMedical University of South CarolinaCharlestonUSA

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