Skip to main content

Engineering and Modeling the Lung Mesenchyme

  • Chapter
  • First Online:
Engineering Translational Models of Lung Homeostasis and Disease

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1413))

Abstract

The structure of the mammalian lung controls the flow of air through the airways and into the distal alveolar region where gas exchange occurs. Specialized cells in the lung mesenchyme produce the extracellular matrix (ECM) and growth factors required for lung structure. Historically, characterizing the mesenchymal cell subtypes was challenging due to their ambiguous morphology, overlapping expression of protein markers, and limited cell-surface molecules needed for isolation. The recent development of single-cell RNA sequencing (scRNA-seq) complemented with genetic mouse models demonstrated that the lung mesenchyme comprises transcriptionally and functionally heterogeneous cell-types. Bioengineering approaches that model tissue structure clarify the function and regulation of mesenchymal cell types. These experimental approaches demonstrate the unique abilities of fibroblasts in mechanosignaling, mechanical force generation, ECM production, and tissue regeneration. This chapter will review the cell biology of the lung mesenchyme and experimental approaches to study their function.

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

Access this chapter

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
USD 29.95
Price excludes VAT (USA)
eBook
USD 149.00
Price excludes VAT (USA)
Hardcover Book
USD 199.99
Price excludes VAT (USA)

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Bellusci, S., Grindley, J., Emoto, H., Itoh, N. & Hogan, B.L. Fibroblast growth factor 10 (FGF10) and branching morphogenesis in the embryonic mouse lung. Development 124, 4867–4878 (1997).

    Article  CAS  PubMed  Google Scholar 

  2. Daley, W.P. & Yamada, K.M. ECM-modulated cellular dynamics as a driving force for tissue morphogenesis. Curr Opin Genet Dev 23, 408–414 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. De Langhe, S.P., et al. Dickkopf-1 (DKK1) reveals that fibronectin is a major target of Wnt signaling in branching morphogenesis of the mouse embryonic lung. Dev Biol 277, 316–331 (2005).

    Article  PubMed  Google Scholar 

  4. Gebb, S.A., Fox, K., Vaughn, J., McKean, D. & Jones, P.L. Fetal oxygen tension promotes tenascin-C-dependent lung branching morphogenesis. Dev Dyn 234, 1–10 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. McCulley, D., Wienhold, M. & Sun, X. The pulmonary mesenchyme directs lung development. Curr Opin Genet Dev 32, 98–105 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Roth-Kleiner, M., Hirsch, E. & Schittny, J.C. Fetal lungs of tenascin-C-deficient mice grow well, but branch poorly in organ culture. Am J Respir Cell Mol Biol 30, 360–366 (2004).

    Article  CAS  PubMed  Google Scholar 

  7. Volckaert, T., et al. Localized Fgf10 expression is not required for lung branching morphogenesis but prevents differentiation of epithelial progenitors. Development 140, 3731–3742 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Whitsett, J.A., Kalin, T.V., Xu, Y. & Kalinichenko, V.V. Building and Regenerating the Lung Cell by Cell. Physiol Rev 99, 513–554 (2019).

    Article  CAS  PubMed  Google Scholar 

  9. Zepp, J.A. & Morrisey, E.E. Cellular crosstalk in the development and regeneration of the respiratory system. Nat Rev Mol Cell Biol 20, 551–566 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Nho, R.S., Ballinger, M.N., Rojas, M.M., Ghadiali, S.N. & Horowitz, J.C. Biomechanical Force and Cellular Stiffness in Lung Fibrosis. Am J Pathol 192, 750–761 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Wolters, P.J., et al. Time for a change: is idiopathic pulmonary fibrosis still idiopathic and only fibrotic? Lancet Respir Med 6, 154–160 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Noble, P.W., Barkauskas, C.E. & Jiang, D. Pulmonary fibrosis: patterns and perpetrators. J Clin Invest 122, 2756–2762 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Somogyi, V., et al. The therapy of idiopathic pulmonary fibrosis: what is next? Eur Respir Rev 28(2019).

    Google Scholar 

  14. Davidson, M.D., Burdick, J.A. & Wells, R.G. Engineered Biomaterial Platforms to Study Fibrosis. Adv Healthc Mater 9, e1901682 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Zepp, J.A., et al. Distinct Mesenchymal Lineages and Niches Promote Epithelial Self-Renewal and Myofibrogenesis in the Lung. Cell 170, 1134–1148 e1110 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lee, J.H., et al. Anatomically and Functionally Distinct Lung Mesenchymal Populations Marked by Lgr5 and Lgr6. Cell 170, 1149–1163 e1112 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zepp, J.A., et al. Genomic, epigenomic, and biophysical cues controlling the emergence of the lung alveolus. Science 371(2021).

    Google Scholar 

  18. Liu, X., et al. Categorization of lung mesenchymal cells in development and fibrosis. iScience 24, 102551 (2021).

    Google Scholar 

  19. Tsukui, T., et al. Collagen-producing lung cell atlas identifies multiple subsets with distinct localization and relevance to fibrosis. Nat Commun 11, 1920 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Adams, T.S., et al. Single-cell RNA-seq reveals ectopic and aberrant lung-resident cell populations in idiopathic pulmonary fibrosis. Sci Adv 6, eaba1983 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Habermann, A.C., et al. Single-cell RNA sequencing reveals profibrotic roles of distinct epithelial and mesenchymal lineages in pulmonary fibrosis. Sci Adv 6, eaba1972 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Basil, M.C., et al. The Cellular and Physiological Basis for Lung Repair and Regeneration: Past, Present, and Future. Cell Stem Cell 26, 482–502 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Tata, P.R. & Rajagopal, J. Plasticity in the lung: making and breaking cell identity. Development 144, 755–766 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wang, C., et al. Expansion of hedgehog disrupts mesenchymal identity and induces emphysema phenotype. J Clin Invest 128, 4343–4358 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  25. O’Hare, K.H. & Sheridan, M.N. Electron microscopic observations on the morphogenesis of the albino rat lung, with special reference to pulmonary epithelial cells. Am J Anat 127, 181–205 (1970).

    Article  PubMed  Google Scholar 

  26. Brody, J.S. & Kaplan, N.B. Proliferation of alveolar interstitial cells during postnatal lung growth. Evidence for two distinct populations of pulmonary fibroblasts. Am Rev Respir Dis 127, 763–770 (1983).

    CAS  PubMed  Google Scholar 

  27. Maksvytis, H.J., et al. In vitro characteristics of the lipid-filled interstitial cell associated with postnatal lung growth: evidence for fibroblast heterogeneity. J Cell Physiol 118, 113–123 (1984).

    Article  CAS  PubMed  Google Scholar 

  28. Barkauskas, C.E., et al. Type 2 alveolar cells are stem cells in adult lung. J Clin Invest 123, 3025–3036 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chung, M.I., Bujnis, M., Barkauskas, C.E., Kobayashi, Y. & Hogan, B.L.M. Niche-mediated BMP/SMAD signaling regulates lung alveolar stem cell proliferation and differentiation. Development 145(2018).

    Google Scholar 

  30. Nabhan, A.N., Brownfield, D.G., Harbury, P.B., Krasnow, M.A. & Desai, T.J. Single-cell Wnt signaling niches maintain stemness of alveolar type 2 cells. Science 359, 1118–1123 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Sun, X., et al. A census of the lung: CellCards from LungMAP. Dev Cell 57, 112–145 e112 (2022).

    Google Scholar 

  32. Sims, D.E. The pericyte--a review. Tissue Cell 18, 153–174 (1986).

    Google Scholar 

  33. Weibel, E.R. On pericytes, particularly their existence on lung capillaries. Microvasc Res 8, 218–235 (1974).

    Article  CAS  PubMed  Google Scholar 

  34. Armulik, A., Genove, G. & Betsholtz, C. Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev Cell 21, 193–215 (2011).

    Article  CAS  PubMed  Google Scholar 

  35. Perros, F., et al. Platelet-derived growth factor expression and function in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 178, 81–88 (2008).

    Article  CAS  PubMed  Google Scholar 

  36. Hellstrom, M., Kalen, M., Lindahl, P., Abramsson, A. & Betsholtz, C. 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, 3047–3055 (1999).

    Article  CAS  PubMed  Google Scholar 

  37. Hung, C., et al. Role of lung pericytes and resident fibroblasts in the pathogenesis of pulmonary fibrosis. Am J Respir Crit Care Med 188, 820–830 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Chandran, R.R., et al. Distinct roles of KLF4 in mesenchymal cell subtypes during lung fibrogenesis. Nat Commun 12, 7179 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Rock, J.R., et al. Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition. Proc Natl Acad Sci U S A 108, E1475–1483 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Volckaert, T., et al. Parabronchial smooth muscle constitutes an airway epithelial stem cell niche in the mouse lung after injury. J Clin Invest 121, 4409–4419 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Moiseenko, A., et al. Identification of a Repair-Supportive Mesenchymal Cell Population during Airway Epithelial Regeneration. Cell Rep 33, 108549 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Gouveia, L., et al. Lung developmental arrest caused by PDGF-A deletion: consequences for the adult mouse lung. Am J Physiol Lung Cell Mol Physiol 318, L831–L843 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kugler, M.C., et al. Sonic Hedgehog Signaling Regulates Myofibroblast Function during Alveolar Septum Formation in Murine Postnatal Lung. Am J Respir Cell Mol Biol 57, 280–293 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Li, C., et al. Secondary crest myofibroblast PDGFRalpha controls the elastogenesis pathway via a secondary tier of signaling networks during alveologenesis. Development 146(2019).

    Google Scholar 

  45. Li, R., Li, X., Hagood, J., Zhu, M.S. & Sun, X. Myofibroblast contraction is essential for generating and regenerating the gas-exchange surface. J Clin Invest 130, 2859–2871 (2020).

    Article  CAS  PubMed  Google Scholar 

  46. Hagan, A.S., et al. Generation and validation of novel conditional flox and inducible Cre alleles targeting fibroblast growth factor 18 (Fgf18). Dev Dyn 248, 882–893 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Jain, R., et al. Plasticity of Hopx(+) type I alveolar cells to regenerate type II cells in the lung. Nat Commun 6, 6727 (2015).

    Article  CAS  PubMed  Google Scholar 

  48. Nikolic, M.Z., et al. Human embryonic lung epithelial tips are multipotent progenitors that can be expanded in vitro as long-term self-renewing organoids. Elife 6(2017).

    Google Scholar 

  49. Gotoh, S., et al. Generation of alveolar epithelial spheroids via isolated progenitor cells from human pluripotent stem cells. Stem Cell Reports 3, 394–403 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Liberti, D.C. & Morrisey, E.E. Organoid models: assessing lung cell fate decisions and disease responses. Trends Mol Med 27, 1159–1174 (2021).

    Article  CAS  PubMed  Google Scholar 

  51. Cassandras, M., et al. Gli1(+) mesenchymal stromal cells form a pathological niche to promote airway progenitor metaplasia in the fibrotic lung. Nat Cell Biol 22, 1295–1306 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kathiriya, J.J., et al. Human alveolar type 2 epithelium transdifferentiates into metaplastic KRT5(+) basal cells. Nat Cell Biol 24, 10–23 (2022).

    Article  CAS  PubMed  Google Scholar 

  53. Chen, Y.W., et al. A three-dimensional model of human lung development and disease from pluripotent stem cells. Nat Cell Biol 19, 542–549 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Strikoudis, A., et al. Modeling of Fibrotic Lung Disease Using 3D Organoids Derived from Human Pluripotent Stem Cells. Cell Rep 27, 3709–3723 e3705 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Tan, Q., Choi, K.M., Sicard, D. & Tschumperlin, D.J. Human airway organoid engineering as a step toward lung regeneration and disease modeling. Biomaterials 113, 118–132 (2017).

    Article  CAS  PubMed  Google Scholar 

  56. Tan, Q., et al. Nascent Lung Organoids Reveal Epithelium- and Bone Morphogenetic Protein-mediated Suppression of Fibroblast Activation. Am J Respir Cell Mol Biol 61, 607–619 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Joshi, R., Batie, M.R., Fan, Q. & Varisco, B.M. Mouse lung organoid responses to reduced, increased, and cyclic stretch. Am J Physiol Lung Cell Mol Physiol 322, L162–L173 (2022).

    Article  CAS  PubMed  Google Scholar 

  58. Dye, B.R., et al. Human lung organoids develop into adult airway-like structures directed by physico-chemical biomaterial properties. Biomaterials 234, 119757 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Hofer, M. & Lutolf, M.P. Engineering organoids. Nat Rev Mater 6, 402–420 (2021).

    Google Scholar 

  60. Huh, D., et al. Reconstituting organ-level lung functions on a chip. Science 328, 1662–1668 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Huh, D., et al. A human disease model of drug toxicity-induced pulmonary edema in a lung-on-a-chip microdevice. Sci Transl Med 4, 159ra147 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Stucki, A.O., et al. A lung-on-a-chip array with an integrated bio-inspired respiration mechanism. Lab Chip 15, 1302–1310 (2015).

    Article  CAS  PubMed  Google Scholar 

  63. Zamprogno, P., et al. Second-generation lung-on-a-chip with an array of stretchable alveoli made with a biological membrane. Commun Biol 4, 168 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Sellgren, K.L., Butala, E.J., Gilmour, B.P., Randell, S.H. & Grego, S. A biomimetic multicellular model of the airways using primary human cells. Lab Chip 14, 3349–3358 (2014).

    Article  CAS  PubMed  Google Scholar 

  65. Huang, D., et al. Reversed-engineered human alveolar lung-on-a-chip model. Proc Natl Acad Sci U S A 118(2021).

    Google Scholar 

  66. Nesmith, A.P., Agarwal, A., McCain, M.L. & Parker, K.K. Human airway musculature on a chip: an in vitro model of allergic asthmatic bronchoconstriction and bronchodilation. Lab Chip 14, 3925–3936 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Mejias, J.C., Nelson, M.R., Liseth, O. & Roy, K. A 96-well format microvascularized human lung-on-a-chip platform for microphysiological modeling of fibrotic diseases. Lab Chip 20, 3601–3611 (2020).

    Article  CAS  PubMed  Google Scholar 

  68. Lagowala, D.A., Kwon, S., Sidhaye, V.K. & Kim, D.H. Human microphysiological models of airway and alveolar epithelia. Am J Physiol Lung Cell Mol Physiol 321, L1072–L1088 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Burgstaller, G., et al. Distinct niches within the extracellular matrix dictate fibroblast function in (cell free) 3D lung tissue cultures. Am J Physiol Lung Cell Mol Physiol 314, L708–L723 (2018).

    Article  CAS  PubMed  Google Scholar 

  70. Gilpin, S.E. & Wagner, D.E. Acellular human lung scaffolds to model lung disease and tissue regeneration. Eur Respir Rev 27(2018).

    Google Scholar 

  71. Booth, A.J., et al. Acellular normal and fibrotic human lung matrices as a culture system for in vitro investigation. Am J Respir Crit Care Med 186, 866–876 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Wagner, D.E., et al. Comparative decellularization and recellularization of normal versus emphysematous human lungs. Biomaterials 35, 3281–3297 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Zhou, Y., et al. Chitinase 3-like 1 suppresses injury and promotes fibroproliferative responses in Mammalian lung fibrosis. Sci Transl Med 6, 240ra276 (2014).

    Article  Google Scholar 

  74. Sava, P., et al. Human pericytes adopt myofibroblast properties in the microenvironment of the IPF lung. JCI Insight 2(2017).

    Google Scholar 

  75. Skibba, M., Drelich, A., Poellmann, M., Hong, S. & Brasier, A.R. Nanoapproaches to Modifying Epigenetics of Epithelial Mesenchymal Transition for Treatment of Pulmonary Fibrosis. Front Pharmacol 11, 607689 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Praphawatvet, T., Peters, J.I. & Williams, R.O., 3rd. Inhaled nanoparticles-An updated review. Int J Pharm 587, 119671 (2020).

    Article  CAS  PubMed  Google Scholar 

  77. Velino, C., et al. Nanomedicine Approaches for the Pulmonary Treatment of Cystic Fibrosis. Front Bioeng Biotechnol 7, 406 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Deng, Z., Kalin, G.T., Shi, D. & Kalinichenko, V.V. Nanoparticle Delivery Systems with Cell-Specific Targeting for Pulmonary Diseases. Am J Respir Cell Mol Biol 64, 292–307 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Kang, H., et al. Size-Dependent EPR Effect of Polymeric Nanoparticles on Tumor Targeting. Adv Healthc Mater 9, e1901223 (2020).

    Article  PubMed  Google Scholar 

  80. Probst, C.K., Montesi, S.B., Medoff, B.D., Shea, B.S. & Knipe, R.S. Vascular permeability in the fibrotic lung. Eur Respir J 56(2020).

    Google Scholar 

  81. Yhee, J.Y., et al. The effects of collagen-rich extracellular matrix on the intracellular delivery of glycol chitosan nanoparticles in human lung fibroblasts. Int J Nanomedicine 12, 6089–6105 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Pandolfi, L., et al. Liposomes Loaded with Everolimus and Coated with Hyaluronic Acid: A Promising Approach for Lung Fibrosis. Int J Mol Sci 22(2021).

    Google Scholar 

  83. Zhang, G., et al. Pulmonary delivery of therapeutic proteins based on zwitterionic chitosan-based nanocarriers for treatment on bleomycin-induced pulmonary fibrosis. Int J Biol Macromol 133, 58–66 (2019).

    Article  CAS  PubMed  Google Scholar 

  84. Kim, J., et al. Lung-targeted delivery of TGF-beta antisense oligonucleotides to treat pulmonary fibrosis. J Control Release 322, 108–121 (2020).

    Article  CAS  PubMed  Google Scholar 

  85. Keum, H., et al. Biomimetic lipid Nanocomplexes incorporating STAT3-inhibiting peptides effectively infiltrate the lung barrier and ameliorate pulmonary fibrosis. J Control Release 332, 160–170 (2021).

    Article  CAS  PubMed  Google Scholar 

  86. Kreyling, W.G., et al. Translocation of ultrafine insoluble iridium particles from lung epithelium to extrapulmonary organs is size dependent but very low. J Toxicol Environ Health A 65, 1513–1530 (2002).

    Article  CAS  PubMed  Google Scholar 

  87. Oberdorster, G. Safety assessment for nanotechnology and nanomedicine: concepts of nanotoxicology. J Intern Med 267, 89–105 (2010).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jarod A. Zepp .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2023 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Snitow, M.E., Chaudhry, F.N., Zepp, J.A. (2023). Engineering and Modeling the Lung Mesenchyme. In: Magin, C.M. (eds) Engineering Translational Models of Lung Homeostasis and Disease. Advances in Experimental Medicine and Biology, vol 1413. Springer, Cham. https://doi.org/10.1007/978-3-031-26625-6_8

Download citation

Publish with us

Policies and ethics