Skip to main content

Advertisement

Springer Nature Link
Log in

Heterogeneity of Fibroblasts and Myofibroblasts in Pulmonary Fibrosis

  • Activated Myofibroblasts and Fibrosis in Various Organs (T Kisseleva and Y Liu, Section Editors)
  • Published:
Current Pathobiology Reports

Abstract

Purpose of Review

Idiopathic pulmonary fibrosis (IPF) is the most common form of interstitial lung disease of unknown etiopathogenesis with mean survival of 3–5 years and limited therapeutics. IPF is characterized by a loss of alveolar type II epithelial cells and aberrant activation of stromal cells, leading to a considerable effort to characterize the origin and activation mechanisms of fibroblasts and myofibroblasts in IPF lungs. In this review, the origin and contribution of fibroblast and myofibroblasts in lung fibrosis will be summarized.

Recent Findings

Lineage tracing experiments suggested that interstitial lung fibroblasts and lipofibroblasts, pericytes, and mesothelial cells differentiate into myofibroblasts. However, epithelial- and bone marrow-derived cells may give rise to collagen expressing cells but may not contribute to the pool of myofibroblasts.

Summary

There is great heterogeneity in fibroblasts and myofibroblasts in fibrotic lungs. Further, there is evidence for the expansion of pericyte-derived myofibroblasts and loss of lipofibroblasts and lipofibroblast-derived myofibroblasts in IPF.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Recently published papers of particular interest have been highlighted as: • Of importance •• Of major importance

  1. Wolters PJ, Collard HR, Jones KD (2014) Pathogenesis of idiopathic pulmonary fibrosis. Annu Rev Pathol 9:157–179. doi:10.1146/annurev-pathol-012513-104706

    Article  CAS  PubMed  Google Scholar 

  2. du Bois RM (2010) Strategies for treating idiopathic pulmonary fibrosis. Nat Rev Drug Discov 9(2):129–140. doi:10.1038/nrd2958

    Article  PubMed  Google Scholar 

  3. King TE Jr (2005) Clinical advances in the diagnosis and therapy of the interstitial lung diseases. Am J Respir Crit Care Med 172(3):268–279. doi:10.1164/rccm.200503-483OE

    Article  PubMed  Google Scholar 

  4. King TE Jr, Pardo A, Selman M (2011) Idiopathic pulmonary fibrosis. Lancet 378(9807):1949–1961. doi:10.1016/S0140-6736(11)60052-4

    Article  PubMed  Google Scholar 

  5. Collard HR, Moore BB, Flaherty KR, Brown KK, Kaner RJ, King TE Jr et al (2007) Acute exacerbations of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 176(7):636–643. doi:10.1164/rccm.200703-463PP

    Article  PubMed  PubMed Central  Google Scholar 

  6. Hogan BL (1999) Morphogenesis Cell 96(2):225–233

    Article  CAS  PubMed  Google Scholar 

  7. Arora R, Metzger RJ, Papaioannou VE (2012) Multiple roles and interactions of Tbx4 and Tbx5 in development of the respiratory system. PLoS Genet 8(8):e1002866. doi:10.1371/journal.pgen.1002866

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. • Xie T, Liang J, Liu N, Huan C, Zhang Y, Liu W et al (2016) Transcription factor TBX4 regulates myofibroblast accumulation and lung fibrosis. J Clin Invest 126(8):3063–3079. doi:10.1172/JCI85328 This study nicely shows the importance of TBX4 as a pulmonary mesodermal transcription factor, where TBX4 lineage-traced cells give rise to multiple stromal lineages in the lung.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Li C, Li M, Li S, Xing Y, Yang CY, Li A et al (2015) Progenitors of secondary crest myofibroblasts are developmentally committed in early lung mesoderm. Stem Cells 33(3):999–1012. doi:10.1002/stem.1911

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Pepicelli CV, Lewis PM, McMahon AP (1998) Sonic hedgehog regulates branching morphogenesis in the mammalian lung. Curr Biol 8(19):1083–1086

    Article  CAS  PubMed  Google Scholar 

  11. Caprioli A, Villasenor A, Wylie LA, Braitsch C, Marty-Santos L, Barry D et al (2015) Wnt4 is essential to normal mammalian lung development. Dev Biol 406(2):222–234. doi:10.1016/j.ydbio.2015.08.017

    Article  CAS  PubMed  Google Scholar 

  12. De Langhe SP, Carraro G, Tefft D, Li C, Xu X, Chai Y et al (2008) Formation and differentiation of multiple mesenchymal lineages during lung development is regulated by beta-catenin signaling. PLoS One 3(1):e1516. doi:10.1371/journal.pone.0001516

    Article  PubMed  PubMed Central  Google Scholar 

  13. Hung C, Linn G, Chow YH, Kobayashi A, Mittelsteadt K, Altemeier WA et al (2013) Role of lung pericytes and resident fibroblasts in the pathogenesis of pulmonary fibrosis. Am J Respir Crit Care Med 188(7):820–830. doi:10.1164/rccm.201212-2297OC

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Rock JR, Barkauskas CE, Cronce MJ, Xue Y, Harris JR, Liang J et al (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. doi:10.1073/pnas.1117988108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Levéen P, Törnell J, Betsholtz C, Pekna M, Pekny M, Lindahl P et al (1996) PDGF-A signaling is a critical event in lung alveolar myofibroblast development and alveogenesis. Cell 85(6):863–873

    Article  PubMed  Google Scholar 

  16. Lindahl P, Karlsson L, Hellstrom M, Gebre-Medhin S, Willetts K, Heath JK et al (1997) Alveogenesis failure in PDGF-A-deficient mice is coupled to lack of distal spreading of alveolar smooth muscle cell progenitors during lung development. Development 124(20):3943–3953

    CAS  PubMed  Google Scholar 

  17. •• Green J, Endale M, Auer H, Perl AK (2016) Diversity of interstitial lung fibroblasts is regulated by platelet-derived growth factor receptor alpha kinase activity. Am J Respir Cell Mol Biol 54(4):532–545. doi:10.1165/rcmb.2015-0095OC Utilizing a PDGFRα lineage tracer, this study nicely shows all of the PDGFRα-derived myofibroblasts in naïve and injured murine lungs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kim N, Vu TH (2006) Parabronchial smooth muscle cells and alveolar myofibroblasts in lung development. Birth Defects Res C Embryo Today 78(1):80–89. doi:10.1002/bdrc.20062

    Article  CAS  PubMed  Google Scholar 

  19. Ramasamy SK, Mailleux AA, Gupte VV, Mata F, Sala FG, Veltmaat JM et al (2007) Fgf10 dosage is critical for the amplification of epithelial cell progenitors and for the formation of multiple mesenchymal lineages during lung development. Dev Biol 307(2):237–247. doi:10.1016/j.ydbio.2007.04.033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yi L, Domyan ET, Lewandoski M, Sun X (2009) Fibroblast growth factor 9 signaling inhibits airway smooth muscle differentiation in mouse lung. Dev Dyn 238(1):123–137. doi:10.1002/dvdy.21831

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Dixit R, Ai X, Fine A (2013) Derivation of lung mesenchymal lineages from the fetal mesothelium requires hedgehog signaling for mesothelial cell entry. Development 140(21):4398–4406. doi:10.1242/dev.098079

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. von Gise A, Stevens SM, Honor LB, Oh JH, Gao C, Zhou B et al (2016) Contribution of fetal, but not adult, pulmonary mesothelium to mesenchymal lineages in lung homeostasis and fibrosis. Am J Respir Cell Mol Biol 54(2):222–230. doi:10.1165/rcmb.2014-0461OC

    Article  Google Scholar 

  23. Torday JS, Torres E, Rehan VK (2003) The role of fibroblast transdifferentiation in lung epithelial cell proliferation, differentiation, and repair in vitro. Pediatr Pathol Mol Med 22(3):189–207

    Article  CAS  PubMed  Google Scholar 

  24. Al Alam D, El Agha E, Sakurai R, Kheirollahi V, Moiseenko A, Danopoulos S et al (2015) Evidence for the involvement of fibroblast growth factor 10 in lipofibroblast formation during embryonic lung development. Development 142(23):4139–4150. doi:10.1242/dev.109173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Varisco BM, Ambalavanan N, Whitsett JA, Hagood JS (2012) Thy-1 signals through PPARgamma to promote lipofibroblast differentiation in the developing lung. Am J Respir Cell Mol Biol 46(6):765–772. doi:10.1165/rcmb.2011-0316OC

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Li A, Ma S, Smith SM, Lee MK, Fischer A, Borok Z et al (2016) Mesodermal ALK5 controls lung myofibroblast versus lipofibroblast cell fate. BMC Biol 14:19. doi:10.1186/s12915-016-0242-9

    Article  PubMed  PubMed Central  Google Scholar 

  27. McQualter JL, Brouard N, Williams B, Baird BN, Sims-Lucas S, Yuen K et al (2009) Endogenous fibroblastic progenitor cells in the adult mouse lung are highly enriched in the sca-1 positive cell fraction. Stem Cells 27(3):623–633. doi:10.1634/stemcells.2008-0866

    Article  CAS  PubMed  Google Scholar 

  28. Ntokou A, Klein F, Dontireddy D, Becker S, Bellusci S, Richardson WD et al (2015) Characterization of the platelet-derived growth factor receptor-alpha-positive cell lineage during murine late lung development. Am J Physiol Lung Cell Mol Physiol 309(9):L942–L958. doi:10.1152/ajplung.00272.2014

    Article  CAS  PubMed  Google Scholar 

  29. •• El Agha E, Moiseenko A, Kheirollahi V, De Langhe S, Crnkovic S, Kwapiszewska G et al (2016) Two-way conversion between lipogenic and myogenic fibroblastic phenotypes marks the progression and resolution of lung fibrosis. Cell Stem Cell. doi:10.1016/j.stem.2016.10.004 This study nicely shows the role of lipofibroblasts in myofibroblast generation in injured murine lungs and the importance of myofibroblast to lipofibroblast transdifferentiation in lung regeneration.

    PubMed  Google Scholar 

  30. • Barron L, Gharib SA, Duffield JS (2016) Lung pericytes and resident fibroblasts: busy multitaskers. Am J Pathol 186(10):2519–2531. doi:10.1016/j.ajpath.2016.07.004 This review nicely highlights the role(s) of pericytes and resident fibroblasts in lung fibrosis.

    Article  PubMed  Google Scholar 

  31. •• Marriott S, Baskir RS, Gaskill C, Menon S, Carrier EJ, Williams J et al (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. doi:10.1152/ajpcell.00114.2014 This study nicely shows the role of ABCG2+ pericytes in murine and human lung fibrosis, where these pericytes can give rise to ACTA2 and collagen 1-expressing myofibroblasts.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lama VN, Phan SH (2006) The extrapulmonary origin of fibroblasts: stem/progenitor cells and beyond. Proc Am Thorac Soc 3(4):373–376. doi:10.1513/pats.200512-133TK

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Phan SH (2012) Genesis of the myofibroblast in lung injury and fibrosis. Proc Am Thorac Soc 9(3):148–152. doi:10.1513/pats.201201-011AW

    Article  CAS  PubMed  Google Scholar 

  34. Gomperts BN, Strieter RM (2007) Fibrocytes in lung disease. J Leukoc Biol 82(3):449–456. doi:10.1189/jlb.0906587

    Article  CAS  PubMed  Google Scholar 

  35. Maharaj S, Shimbori C, Kolb M (2013) Fibrocytes in pulmonary fibrosis: a brief synopsis. Eur Respir Rev 22(130):552–557. doi:10.1183/09059180.00007713

    Article  PubMed  Google Scholar 

  36. Hashimoto N, Jin H, Liu T, Chensue SW, Phan SH (2004) Bone marrow-derived progenitor cells in pulmonary fibrosis. J Clin Invest 113(2):243–252. doi:10.1172/JCI18847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Epperly MW, Guo H, Gretton JE, Greenberger JS (2003) Bone marrow origin of myofibroblasts in irradiation pulmonary fibrosis. Am J Respir Cell Mol Biol 29(2):213–224. doi:10.1165/rcmb.2002-0069OC

    Article  CAS  PubMed  Google Scholar 

  38. • Sontake V, Shanmukhappa SK, DiPasquale BA, Reddy GB, Medvedovic M, Hardie WD et al (2015) Fibrocytes regulate Wilms tumor 1-positive cell accumulation in severe fibrotic lung disease. J Immunol 195(8):3978–3991. doi:10.4049/jimmunol.1500963 This study nicely shows a novel role for fibrocytes, where these cells contribute to the activation of Wilms tumor 1+ mesothelial cells in remodeled murine lungs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Karki S, Surolia R, Hock TD, Guroji P, Zolak JS, Duggal R et al (2014) Wilms’ tumor 1 (Wt1) regulates pleural mesothelial cell plasticity and transition into myofibroblasts in idiopathic pulmonary fibrosis. FASEB J 28(3):1122–1131. doi:10.1096/fj.13-236828

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zolak JS, Jagirdar R, Surolia R, Karki S, Oliva O, Hock T et al (2013) Pleural mesothelial cell differentiation and invasion in fibrogenic lung injury. Am J Pathol 182(4):1239–1247. doi:10.1016/j.ajpath.2012.12.030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Mubarak KK, Montes-Worboys A, Regev D, Nasreen N, Mohammed KA, Faruqi I et al (2012) Parenchymal trafficking of pleural mesothelial cells in idiopathic pulmonary fibrosis. Eur Respir J 39(1):133–140. doi:10.1183/09031936.00141010

    Article  CAS  PubMed  Google Scholar 

  42. • Xu Y, Mizuno T, Sridharan A, Du Y, Guo M, Tang J et al (2016) Single-cell RNA sequencing identifies diverse roles of epithelial cells in idiopathic pulmonary fibrosis. JCI Insight 1(20):e90558. doi:10.1172/jci.insight.90558 Utilizing single-cell RNA sequencing, this study nicely shows the presence of basal-like cells in IPF lungs co-expressing mesenchymal markers. This is the first study to provide strong evidence for mesenchymal transcript expression in basal cells from IPF but not normal lung explants.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Tanjore H, Xu XC, Polosukhin VV, Degryse AL, Li B, Han W et al (2009) Contribution of epithelial-derived fibroblasts to bleomycin-induced lung fibrosis. Am J Respir Crit Care Med 180(7):657–665. doi:10.1164/rccm.200903-0322OC

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kim KK, Kugler MC, Wolters PJ, Robillard L, Galvez MG, Brumwell AN et al (2006) Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc Natl Acad Sci U S A 103(35):13180–13185. doi:10.1073/pnas.0605669103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Degryse AL, Tanjore H, Xu XC, Polosukhin VV, Jones BR, McMahon FB et al (2010) Repetitive intratracheal bleomycin models several features of idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 299(4):L442–L452. doi:10.1152/ajplung.00026.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Wu Z, Yang L, Cai L, Zhang M, Cheng X, Yang X et al (2007) Detection of epithelial to mesenchymal transition in airways of a bleomycin induced pulmonary fibrosis model derived from an alpha-smooth muscle actin-Cre transgenic mouse. Respir Res 8:1. doi:10.1186/1465-9921-8-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Liang J, Zhang Y, Xie T, Liu N, Chen H, Geng Y et al (2016) Hyaluronan and TLR4 promote surfactant-protein-C-positive alveolar progenitor cell renewal and prevent severe pulmonary fibrosis in mice. Nat Med 22(11):1285–1293. doi:10.1038/nm.4192

    Article  CAS  PubMed  Google Scholar 

  48. Bartis D, Crowley LE, D'Souza VK, Borthwick L, Fisher AJ, Croft AP et al (2016) Role of CD248 as a potential severity marker in idiopathic pulmonary fibrosis. BMC Pulm Med 16(1):51. doi:10.1186/s12890-016-0211-7

    Article  PubMed  PubMed Central  Google Scholar 

  49. Naylor AJ, Azzam E, Smith S, Croft A, Poyser C, Duffield JS et al (2012) The mesenchymal stem cell marker CD248 (endosialin) is a negative regulator of bone formation in mice. Arthritis Rheum 64(10):3334–3343. doi:10.1002/art.34556

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Smith SW, Croft AP, Morris HL, Naylor AJ, Huso DL, Isacke CM et al (2015) Genetic deletion of the stromal cell marker CD248 (endosialin) protects against the development of renal fibrosis. Nephron 131(4):265–277. doi:10.1159/000438754

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Iwayama T, Steele C, Yao L, Dozmorov MG, Karamichos D, Wren JD et al (2015) PDGFRalpha signaling drives adipose tissue fibrosis by targeting progenitor cell plasticity. Genes Dev 29(11):1106–1119. doi:10.1101/gad.260554.115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Chen L, Acciani T, Le Cras T, Lutzko C, Perl AK (2012) Dynamic regulation of platelet-derived growth factor receptor alpha expression in alveolar fibroblasts during realveolarization. Am J Respir Cell Mol Biol 47(4):517–527. doi:10.1165/rcmb.2012-0030OC

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Chen LJ, Ye H, Zhang Q, Li FZ, Song LJ, Yang J et al (2015) Bleomycin induced epithelial-mesenchymal transition (EMT) in pleural mesothelial cells. Toxicol Appl Pharmacol 283(2):75–82. doi:10.1016/j.taap.2015.01.004

    Article  CAS  PubMed  Google Scholar 

  54. Herzog EL, Bucala R (2010) Fibrocytes in health and disease. Exp Hematol 38(7):548–556. doi:10.1016/j.exphem.2010.03.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Habiel DM, Hogaboam C (2014) Heterogeneity in fibroblast proliferation and survival in idiopathic pulmonary fibrosis. Front Pharmacol 5:2. doi:10.3389/fphar.2014.00002

    Article  PubMed  PubMed Central  Google Scholar 

  56. Srour N, Thebaud B (2015) Mesenchymal stromal cells in animal bleomycin pulmonary fibrosis models: a systematic review. Stem Cells Transl Med 4(12):1500–1510. doi:10.5966/sctm.2015-0121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Chambers DC, Enever D, Ilic N, Sparks L, Whitelaw K, Ayres J et al (2014) A phase 1b study of placenta-derived mesenchymal stromal cells in patients with idiopathic pulmonary fibrosis. Respirology 19(7):1013–1018. doi:10.1111/resp.12343

    Article  PubMed  Google Scholar 

  58. Bucala R, Spiegel LA, Chesney J, Hogan M, Cerami A (1994) Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair. Mol Med 1(1):71–81

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Schmidt M, Sun G, Stacey MA, Mori L, Mattoli S (2003) Identification of circulating fibrocytes as precursors of bronchial myofibroblasts in asthma. J Immunol 171(1):380–389

    Article  CAS  PubMed  Google Scholar 

  60. Phillips RJ, Burdick MD, Hong K, Lutz MA, Murray LA, Xue YY et al (2004) Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis. J Clin Invest 114(3):438–446. doi:10.1172/JCI20997

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Shi Y, Ou L, Han S, Li M, Pena MM, Pena EA et al (2014) Deficiency of Kruppel-like factor KLF4 in myeloid-derived suppressor cells inhibits tumor pulmonary metastasis in mice accompanied by decreased fibrocytes. Oncogene 3:e129. doi:10.1038/oncsis.2014.44

    Article  CAS  Google Scholar 

  62. Ou L, Shi Y, Dong W, Liu C, Schmidt TJ, Nagarkatti P et al (2015) Kruppel-like factor KLF4 facilitates cutaneous wound healing by promoting fibrocyte generation from myeloid-derived suppressor cells. J Invest Dermatol 135(5):1425–1434. doi:10.1038/jid.2015.3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Fernandez IE, Greiffo FR, Frankenberger M, Bandres J, Heinzelmann K, Neurohr C et al (2016) Peripheral blood myeloid-derived suppressor cells reflect disease status in idiopathic pulmonary fibrosis. Eur Respir J 48(4):1171–1183. doi:10.1183/13993003.01826-2015

    Article  PubMed  Google Scholar 

  64. Trujillo G, Hartigan AJ, Hogaboam CM (2010) T regulatory cells and attenuated bleomycin-induced fibrosis in lungs of CCR7−/− mice. Fibrogenesis Tissue Repair 3:18. doi:10.1186/1755-1536-3-18

    Article  PubMed  PubMed Central  Google Scholar 

  65. Mehrad B, Burdick MD, Zisman DA, Keane MP, Belperio JA, Strieter RM (2007) Circulating peripheral blood fibrocytes in human fibrotic interstitial lung disease. Biochem Biophys Res Commun 353(1):104–108. doi:10.1016/j.bbrc.2006.11.149

    Article  CAS  PubMed  Google Scholar 

  66. Andersson-Sjoland A, de Alba CG, Nihlberg K, Becerril C, Ramirez R, Pardo A et al (2008) Fibrocytes are a potential source of lung fibroblasts in idiopathic pulmonary fibrosis. Int J Biochem Cell Biol 40(10):2129–2140. doi:10.1016/j.biocel.2008.02.012

    Article  PubMed  Google Scholar 

  67. Hogaboam CM, Murray L, Martinez FJ (2012) Epigenetic mechanisms through which toll-like receptor-9 drives idiopathic pulmonary fibrosis progression. Proc Am Thorac Soc 9(3):172–176. doi:10.1513/pats.201201-002AW

    Article  CAS  PubMed  Google Scholar 

  68. Huang SK, Scruggs AM, McEachin RC, White ES, Peters-Golden M (2014) Lung fibroblasts from patients with idiopathic pulmonary fibrosis exhibit genome-wide differences in DNA methylation compared to fibroblasts from nonfibrotic lung. PLoS One 9(9):e107055. doi:10.1371/journal.pone.0107055

    Article  PubMed  PubMed Central  Google Scholar 

  69. Sanders YY, Liu H, Scruggs AM, Duncan SR, Huang SK, Thannickal VJ (2017) Epigenetic regulation of caveolin-1 gene expression in lung fibroblasts. Am J Respir Cell Mol Biol 56(1):50–61. doi:10.1165/rcmb.2016-0034OC

    Article  PubMed  Google Scholar 

  70. Xiao X, Senavirathna LK, Gou X, Huang C, Liang Y, Liu L (2016) EZH2 enhances the differentiation of fibroblasts into myofibroblasts in idiopathic pulmonary fibrosis. Physiol Rep 4(17):e12915. doi:10.14814/phy2.12915

    Article  PubMed  PubMed Central  Google Scholar 

  71. Korfei M, Skwarna S, Henneke I, MacKenzie B, Klymenko O, Saito S et al (2015) Aberrant expression and activity of histone deacetylases in sporadic idiopathic pulmonary fibrosis. Thorax 70(11):1022–1032. doi:10.1136/thoraxjnl-2014-206411

    Article  PubMed  Google Scholar 

  72. Sanders YY, Liu H, Liu G, Thannickal VJ (2015) Epigenetic mechanisms regulate NADPH oxidase-4 expression in cellular senescence. Free Radic Biol Med 79:197–205. doi:10.1016/j.freeradbiomed.2014.12.008

    Article  CAS  PubMed  Google Scholar 

  73. O'Dwyer DN, Armstrong ME, Trujillo G, Cooke G, Keane MP, Fallon PG et al (2013) The toll-like receptor 3 L412F polymorphism and disease progression in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 188(12):1442–1450. doi:10.1164/rccm.201304-0760OC

    Article  PubMed  Google Scholar 

  74. Hecker L, Logsdon NJ, Kurundkar D, Kurundkar A, Bernard K, Hock T et al (2014) Reversal of persistent fibrosis in aging by targeting Nox4-Nrf2 redox imbalance. Sci Transl Med 6(231):231ra47. doi:10.1126/scitranslmed.3008182

    Article  PubMed  PubMed Central  Google Scholar 

  75. Im J, Kim K, Hergert P, Nho RS (2016) Idiopathic pulmonary fibrosis fibroblasts become resistant to Fas ligand-dependent apoptosis via the alteration of decoy receptor 3. J Pathol 240(1):25–37. doi:10.1002/path.4749

    Article  CAS  PubMed  Google Scholar 

  76. Moodley YP, Misso NL, Scaffidi AK, Fogel-Petrovic M, McAnulty RJ, Laurent GJ et al (2003) Inverse effects of interleukin-6 on apoptosis of fibroblasts from pulmonary fibrosis and normal lungs. Am J Respir Cell Mol Biol 29(4):490–498. doi:10.1165/rcmb.2002-0262OC

    Article  CAS  PubMed  Google Scholar 

  77. Scaffidi AK, Mutsaers SE, Moodley YP, McAnulty RJ, Laurent GJ, Thompson PJ et al (2002) Oncostatin M stimulates proliferation, induces collagen production and inhibits apoptosis of human lung fibroblasts. Br J Pharmacol 136(5):793–801. doi:10.1038/sj.bjp.0704769

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Ebener S, Barnowski S, Wotzkow C, Marti TM, Lopez-Rodriguez E, Crestani B et al Toll-like receptor 4 (TLR4) activation attenuates pro-fibrotic response in control lung fibroblasts but not in fibroblasts from IPF patients. Am J Physiol Lung Cell Mol Physiol. doi:10.1152/ajplung.00119.2016

  79. Meneghin A, Choi ES, Evanoff HL, Kunkel SL, Martinez FJ, Flaherty KR et al (2008) TLR9 is expressed in idiopathic interstitial pneumonia and its activation promotes in vitro myofibroblast differentiation. Histochem Cell Biol 130(5):979–992. doi:10.1007/s00418-008-0466-z

    Article  CAS  PubMed  Google Scholar 

  80. Trujillo G, Meneghin A, Flaherty KR, Sholl LM, Myers JL, Kazerooni EA et al (2010) TLR9 differentiates rapidly from slowly progressing forms of idiopathic pulmonary fibrosis. Sci Transl Med 2(57):57ra82. doi:10.1126/scitranslmed.3001510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Chilosi M, Zamo A, Doglioni C, Reghellin D, Lestani M, Montagna L et al (2006) Migratory marker expression in fibroblast foci of idiopathic pulmonary fibrosis. Respir Res 7:95. doi:10.1186/1465-9921-7-95

    Article  PubMed  PubMed Central  Google Scholar 

  82. Kirillov V, Siler JT, Ramadass M, Ge L, Davis J, Grant G et al (2015) Sustained activation of toll-like receptor 9 induces an invasive phenotype in lung fibroblasts: possible implications in idiopathic pulmonary fibrosis. Am J Pathol 185(4):943–957. doi:10.1016/j.ajpath.2014.12.011

    Article  CAS  PubMed  Google Scholar 

  83. Li Y, Jiang D, Liang J, Meltzer EB, Gray A, Miura R et al (2011) Severe lung fibrosis requires an invasive fibroblast phenotype regulated by hyaluronan and CD44. J Exp Med 208(7):1459–1471. doi:10.1084/jem.20102510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Ahluwalia N, Grasberger PE, Mugo BM, Feghali-Bostwick C, Pardo A, Selman M et al (2016) Fibrogenic lung injury induces non-cell-autonomous fibroblast invasion. Am J Respir Cell Mol Biol 54(6):831–842. doi:10.1165/rcmb.2015-0040OC

    Article  CAS  PubMed  Google Scholar 

  85. Cai GQ, Zheng A, Tang Q, White ES, Chou CF, Gladson CL et al (2010) Downregulation of FAK-related non-kinase mediates the migratory phenotype of human fibrotic lung fibroblasts. Exp Cell Res 316(9):1600–1609. doi:10.1016/j.yexcr.2010.01.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Suganuma H, Sato A, Tamura R, Chida K (1995) Enhanced migration of fibroblasts derived from lungs with fibrotic lesions. Thorax 50(9):984–989

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Shea BS, Tager AM (2012) Role of the lysophospholipid mediators lysophosphatidic acid and sphingosine 1-phosphate in lung fibrosis. Proc Am Thorac Soc 9(3):102–110. doi:10.1513/pats.201201-005AW

    Article  CAS  PubMed  Google Scholar 

  88. Jun D, Garat C, West J, Thorn N, Chow K, Cleaver T et al (2011) 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(4):725–735. doi:10.1002/stem.604

    Article  PubMed  PubMed Central  Google Scholar 

  89. Leaf IA, Nakagawa S, Johnson BG, Cha JJ, Mittelsteadt K, Guckian KM et al (2016) Pericyte MyD88 and IRAK4 control inflammatory and fibrotic responses to tissue injury. J Clin Invest. doi:10.1172/JCI87532

    PubMed  PubMed Central  Google Scholar 

  90. Chanda D, Kurundkar A, Rangarajan S, Locy M, Bernard K, Sharma NS et al (2016) Developmental reprogramming in mesenchymal stromal cells of human subjects with idiopathic pulmonary fibrosis. Sci Rep 6:37445. doi:10.1038/srep37445

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Cedars-Sinai Medical Center, 127 S San Vicente Blvd, AHSP 9404, Los Angeles, CA, 90048, USA

    David M. Habiel & Cory M. Hogaboam

Authors
  1. David M. Habiel
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Cory M. Hogaboam
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to David M. Habiel.

Ethics declarations

Conflict of Interest

David Habiel and Cory Hogaboam declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Activated Myofibroblasts and Fibrosis in Various Organs

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Habiel, D.M., Hogaboam, C.M. Heterogeneity of Fibroblasts and Myofibroblasts in Pulmonary Fibrosis. Curr Pathobiol Rep 5, 101–110 (2017). https://doi.org/10.1007/s40139-017-0134-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40139-017-0134-x

Keywords