Amnion Epithelial Cells for Lung Diseases

Fig. 19.1
Human amnion epithelial cells (hAECs) promote tissue repair via the modulation of host immune cells. Through the secretion of lipoxins and other mediators, hAECs polarize M1 macrophages to M2 phenotype thereby increasing phagocytosis and promoting resolution of injury. Via numerous soluble mediators such as HLA-G, prostaglandins and IDO, hAECs inhibit T-cell proliferation and likely convert effector T cells to Th2 cells, thereby promoting repair

4.2 Soluble Mediators

Insights into the likely mediators of the reparative properties of hAECs may arise from the observation that while term hAECs are highly effective at preventing bleomycin lung injury, hAECs derived from preterm amnion are not [72]. Preterm hAECs are much more proliferative than term hAECs but, despite extended culture in SAGM, do not switch on surfactant protein expression [45]. Importantly, while term hAECs reduce lung inflammation and fibrosis following bleomycin preterm hAECs do not [45]. Surprisingly, while preterm hAECs were not as effective as term hAECs at inhibiting macrophage recruitment to the injured lung, they did mitigate recruitment somewhat. Whether preterm hAECs can modulate macrophage polarization has not yet been reported. There are likely to be many differences in the factors secreted by preterm and term hAECs that might underlie their differential reparative properties. One possible candidate is HLA-G. HLA-G is a nonclassical immunosuppressive HLA class I molecule [73]. It inhibits the functions of both NK and cytotoxic T cells and induces T regulatory cells (Tregs) [74, 75] (Fig. 19.1). While there are no reports yet that HLA-G mediates the effects of amnion cells, amnion cells do secrete HLA-G [76] and other placental cells are able to modulate immune cell function via HLA-G [77]. Importantly, preterm hAECs secrete less HLA-G than term hAECs [45]. Whether HLA-G is a key mediator awaits further study.

Amnion epithelial cells secrete many other candidate mediators including prostaglandins, indolamine (IDO), and numerous cytokines [34] (Fig. 19.1). Much detailed work lies ahead to determine which of these are required for the immunomodulatory properties of the cells.

4.3 Other Mechanisms

In addition to their immunosuppressive activities, hAECs are likely to exert their reparative effects via other mechanisms. For example, hAECs can directly reduce fibroblast proliferation and activation [40] and amnion stromal cells are able to reverse the myofibroblasts away from profibrotic phenotype [78]. Given the central role that fibroblast play in lung fibrosis these direct effects are likely to be highly beneficial.

It is also possible that hAECs may induce the proliferation of endogenous lung progenitor cells, as has been observed for MSCs [79]. Thus, through the recruitment of host lung progenitor cells hAECs could accelerate repair following injury. Whether hAECs possess such an ability also awaits examination.

5 Summary

hAECs are an abundant and safe source of cells for regenerative medicine. They have proven roles in the prevention and repair of experimental lung injury in both adult and neonatal models and in both acute and chronic injury. While hAECs are certainly able to integrate into injured lung epithelium and differentiate into lung cells, it would appear that they most likely exert their reparative effects via the modulation of host immune cells, particularly host macrophages. There is much yet to be learned about the properties of hAECs and how they might be best used. Given their abundance and safety record, clinical trials of hAECs in lung diseases appear to be relatively straightforward. Hopefully, the next 5 years or so will reveal whether these cells provide us with a whole new therapeutic armamentarium.


The authors acknowledge financial support from the National Health and Medical Research Council (NHMRC) Australia, The Royal Australian and New Zealand College of Obstetricians and Gynaecologists Research Foundation and the Victorian Government’s Operational Infrastructure Support Program.



World Health Organization. World Health Statistics 2013. Geneva: World Health Organization; 2013.


Access Economics. Economic impact of COPD and cost effective solutions. A report for the Australian Lung Foundation. Access Economics 2008. http://​www.​lungfoundation.​com.​au/​lung-information/​publications/​economic-impact-of-copd-2008


Akinbami LJ, Liu X. Chronic obstructive pulmonary disease among adults aged 18 and over in the United States, 1998–2009. NCHS data brief, no 63. Hyattsville, MD: National Center for Health Statistics; 2011.


Centers for Disease Control and Prevention. Chronic obstructive pulmonary disease among adults—United States, 2011. MMWR Morb Mortal Wkly Rep. 2012;61:938–943. http://​www.​cdc.​gov/​mmwr/​pdf/​wk/​mm6146.​pdf


National Heart, Lung, and Blood Institute, and National Institutes of Health. Morbidity and mortality: 2004 chartbook on cardiovascular, lung, and blood diseases, Bethesda, MD; 2005.


Foster TA, Miller JD, Marton JP, Caloyeras JP, Russell MW, Menzin J. Assessment of the economic burden of COPD in the US: a review and synthesis of the literature. COPD. 2006;3:211–8.PubMedCrossRef


Baraldi E, Filippone M. Chronic lung disease after premature birth. N Engl J Med. 2007;357:1946–55.PubMedCrossRef


Van Marter LJ. Epidemiology of bronchopulmonary dysplasia. Semin Fetal Neonatal Med. 2009;14:358–66.PubMedCrossRef


Smith VC, Zupancic JA, McCormick MC, Croen LA, Greene J, Escobar GJ, Richardson DK. Trends in severe bronchopulmonary dysplasia rates between 1994 and 2002. J Pediatr. 2005;146:469–73.PubMedCrossRef


Jobe AH. The new BPD. Neoreviews. 2006;7:e531–45.CrossRef


McAleese KA, Knapp MA, Rhodes TT. Financial and emotional cost of bronchopulmonary dysplasia. Clin Pediatr. 1993;32: 393–400.CrossRef


Hennessy EM, Bracewell MA, Wood N, Wolke D, Costeloe K, Gibson A, Marlow N. Respiratory health in pre-school and school age children following extremely preterm birth. Arch Dis Child. 2008;93(12):1037–43.PubMedCrossRef


Bourbeau J, Johnson M. New and controversial therapies for chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2009;6:553–4.PubMedCrossRef


Sueblinvong V, Weiss DJ. Stem cells and cell therapy approaches in lung biology and diseases. Transplant Res. 2010;156:188–205.


Vosdoganes P, Lim R, Moss TJM, Wallace EM. Cell therapy: a novel treatment for bronchopulmonary dysplasia. Pediatrics. 2012; 130:727–37.PubMedCrossRef


Weiss DJ, Bertoncello I, Borok Z, Kim C, Panoskaltsis-Mortari A, Reynolds S, Rojas M, Stripp B, Warburton D, Prockop DJ. Stem cells and sell therapies in lung biology and lung diseases. Proc Am Thorac Soc. 2011;8:223–72.PubMedCentralPubMedCrossRef


Parolini O, Alviano F, Bagnara GP, Bilic G, Buhring HJ, Evangelista M, et al. Concise review: isolation and characterization of cells from human term placenta: outcome of the first international workshop on placenta derived stem cells. Stem Cells. 2008;26:300–11.PubMedCrossRef


Fauza D. Amniotic fluid and placental stem cells. Best Pract Res Clin Obstet Gynaecol. 2004;18:877–91.PubMedCrossRef


Murphy S, Rosli S, Acharya R, Mathias L, Lim R, Wallace E, Jenkin G. Amnion epithelial cell isolation and characterization for clinical use. Curr Protoc Stem Cell Biol. 2010;Chapter 1:1E6.1–6.25.


Murphy S, Wallace E, Jenkin G. Placental-derived stem cells: potential clinical applications. In: Appasani K, Appasani RK, editors. Stem cells and regenerative medicine. New York: Springer Science + Business Media, LLC; 2011. p. 243–63.


Ilancheran S, Michalska A, Peh G, Wallace EM, Pera M, Manuelpillai U. Stem cells derived from human fetal membranes display multilineage differentiation potential. Biol Reprod. 2007;77:577–88.PubMedCrossRef


Izumi M, Pazin B, Minervini CF, Gerlach J, Ross M, Stolz DB, Turner ME, Thompson RL, Miki T. Quantitative comparison of stem cell marker-positive cells in fetal and term human amnion. J Reprod Immunol. 2009;81:39–43.PubMedCrossRef


Miki T, Lehmann T, Cai H, Stolz DB, Strom SC. Stem cell characteristics of amniotic epithelial cells. Stem Cells. 2005;23:1549–59.PubMedCrossRef


Tamagawa T, Ishiwata I, Saito S. Establishment and characterization of a pluripotent stem cell line derived from human amniotic membranes and initiation of germ layers in vitro. Hum Cell. 2004;17:125–30.PubMedCrossRef


Trounson A, Pera M. Human embryonic stem cells. Fertil Steril. 2001;76:660–1.PubMedCrossRef

Mar 22, 2018 | Posted by in BIOCHEMISTRY | Comments Off on Amnion Epithelial Cells for Lung Diseases

Full access? Get Clinical Tree

Get Clinical Tree app for offline access