Placenta-derived cells: A new source for regenerative medicine application

Abstract

The placenta is the first and most important organ of pregnancy. It is the communication bridge between the mother and fetus. Placental elements, due to their important position and function, are specially designed to manage the exchange of nutrients and the local regulation of the maternal immune system. The development of cells such as cytotrophoblasts, syncytiotrophoblasts, extravillous trophoblasts, placental giant trophoblasts, placental macrophages, and placenta-derived mesenchymal stromal cells is described. Medical researches have been performed to demonstrate the curative potential properties of these cells, such as treating burns, tendon and joint diseases, lung diseases, blood and bone marrow diseases, and other diseases. This review provides an overview of the formation and development of placental cell lines and their potential for regenerative medicinal research and ongoing clinical applications.23-01-2024

Keywords

• Placenta
• Placental MSC
• Application
• Clinical trial

References

1. Turco MY, Moffett A. Development of the human placenta. Development 2019; 146: dev163428. doi:10.1242/dev.163428.
2. Carlson BM. Placenta. Reference Module in Biomedical Sciences. Elsevier, 2014.
3. Sferruzzi-Perri AN, Camm EJ. The programming power of the placenta. Front Physiol 2016; 7: 33. doi:10.3389/ fphys.2016.00033.
4. Brosens I, Pijnenborg R, Vercruysse L, Romero R. The “Great Obstetrical Syndromes” are associated with disorders of deep placentation. Am J Obstet Gynecol 2011; 204: 193-201. doi:10.1016/j.ajog.2010.08.009.
5. Burton GJ, Fowden AL. The placenta: a multifaceted, transient organ. Phil Trans R Soc B 2015; 370: 20140066. doi:10.1098/ rstb.2014.0066
6. Hemberger M, Hanna CW, Dean W. Mechanisms of early placental development in mouse and humans. Nat Rev Genet 2020; 21: 27-43. doi:10.1038/s41576.019.0169-4.
7. Carter AM, Enders AC, Pijnenborg R. The role of invasive trophoblast in implantation and placentation of primates. Philos Trans R Soc Lond B Biol Sci 2015; 370: 20140070. doi:10.1098/rstb.2014.0070.
8. Cuman C, Menkhorst E, Winship A, et al. Fetal-maternal communication: the role of Notch signalling in embryo implantation. Reproduction 2014; 147: R75-86. doi:10.1530/ rep-13-0474.

9. Lee C, Moulvi A, James JL, Clark AR. Multi-scale modelling of shear stress on the syncytiotrophoblast: Could maternal blood flow impact placental function across gestation? Ann Biomed Eng 2023; 51: 1256-1269. doi:10.1007/s10439.022.03129-2.
10. Aplin JD, Myers JE, Timms K, Westwood M. Tracking placental development in health and disease. Nat Rev Endocrinol 2020; 16: 479-494. doi:10.1038/s41574.020.0372-6.
11. Ashton V, Whitley GS, Dash PR, et al. Uterine spiral artery remodeling involves endothelial apoptosis induced by extravillous trophoblasts through Fas/FasL interactions. Arterioscler Thromb Vasc Biol 2005; 25: 102-8. doi:10.1161/01. Atv.000.014.8547.70187.89.
12. Whitley GS, Cartwright JE. Trophoblast-mediated spiral artery remodelling: a role for apoptosis. J Anat 2009; 215: 21- 6. doi:10.1111/j.1469-7580.2008.01039.x.
13. Burton GJ, Woods AW, Jauniaux E, Kingdom JC. Rheological and physiological consequences of conversion of the maternal spiral arteries for uteroplacental blood flow during human pregnancy. Placenta 2009; 30: 473-82. doi:10.1016/j. placenta.2009.02.009.
14. Kaufmann P, Black S, Huppertz B. Endovascular trophoblast invasion: implications for the pathogenesis of intrauterine growth retardation and preeclampsia. Biol Reprod 2003; 69: 1-7. doi:10.1095/biolreprod.102.014977.
15. Lyall F, Robson SC, Bulmer JN. Spiral artery remodeling and trophoblast invasion in preeclampsia and fetal growth restriction: relationship to clinical outcome. Hypertension 2013; 62: 1046-54. doi:10.1161/hypertensionaha.113.01892.
16. Burton GJ, Fowden AL. The placenta: a multifaceted, transient organ. Philos Trans R Soc Lond B Biol Sci 2015; 370: 20140066. doi:10.1098/rstb.2014.0066.
17. James JL, Carter AM, Chamley LW. Human placentation from nidation to 5 weeks of gestation. Part I: What do we know about formative placental development following implantation? Placenta 2012; 33: 327-34. doi:10.1016/j.placenta.2012.01.020.
18. Roberts KA, Riley SC, Reynolds RM, et al. Placental structure and inflammation in pregnancies associated with obesity. Placenta 2011; 32: 247-54. doi:10.1016/j.placenta.2010.12.023.
19. Fournier T. Human chorionic gonadotropin: Different glycoforms and biological activity depending on its source of production. Ann Endocrinol (Paris) 2016; 77: 75-81. doi:10.1016/j.ando.2016.04.012.
20. Strott CA, Yoshimi T, Ross GT, Lipsett MB. Ovarian physiology: relationship between plasma LH and steroidogenesis by the follicle and corpus luteum; effect of HCG. J Clin Endocrinol Metab 1969; 29: 1157-67. doi:10.1210/jcem-29-9-1157.
21. Lee B, Park TC, Lee HJ. Maternal age and serum concentration of human chorionic gonadotropin in early pregnancy: influence of gonadotropin-releasing hormone. Acta Obstet Gynecol Scand 2015; 94: 443-4. doi:10.1111/aogs.12573.
22. Alsat E, Bouali Y, Goldstein S, Malassiné A, Laudat MH, Cedard L. Characterization of specific low-density lipoprotein binding sites in human term placental microvillous membranes. Mol Cell Endocrinol 1982; 28: 439-53. doi:10.1016/0303- 7207(82)90138-1.
23. Spaans F, Kao CK, Morton JS, et al. Syncytiotrophoblast extracellular vesicles impair rat uterine vascular function via the lectin-like oxidized LDL receptor-1. PLoS One 2017; 12: e0180364. doi:10.1371/journal.pone.0180364.
24. Musicki B, Pepe GJ, Albrecht ED. Functional differentiation of the placental syncytiotrophoblast: Effect of estrogen on chorionic somatomammotropin expression during early primate pregnancy. The Journal of Clinical Endocrinology & Metabolism 2003; 88: 4316-4323. doi:10.1210/jc.2002-022052.
25. Pedersen AM, Taylor BK, Payne AM, Abdelrahim M, Francis GL. Macrophage conditioned media affects steroid hormone production by placental cultures. Ann Clin Lab Sci 1994; 24: 548-54.
26. Ruch RJ. The role of gap junctional intercellular communication in neoplasia. Ann Clin Lab Sci 1994; 24: 216-31.
27. Adler RR, Ng AK, Rote NS. Monoclonal antiphosphatidylserine antibody inhibits intercellular fusion of the choriocarcinoma line, JAR. Biol Reprod 1995; 53: 905-10. doi:10.1095/ biolreprod53.4.905.
28. Manaster I, Mandelboim O. The unique properties of uterine NK cells. Am J Reprod Immunol 2010; 63: 434-44. doi:10.1111/ j.1600-0897.2009.00794.x.
29. Liu S, Diao L, Huang C, Li Y, Zeng Y, Kwak-Kim JYH. The role of decidual immune cells on human pregnancy. J Reprod Immunol 2017; 124: 44-53. doi:10.1016/j.jri.2017.10.045.
30. Tilburgs T, Meissner TB, Ferreira LMR, et al. NLRP2 is a suppressor of NF-ƙB signaling and HLA-C expression in human trophoblasts†,‡. Biol Reprod 2017; 96: 831-842. doi:10.1093/biolre/iox009.
31. Ljunggren HG, Kärre K. In search of the ‘missing self ’: MHC molecules and NK cell recognition. Immunol Today 1990; 11: 237-44. doi:10.1016/0167-5699(90)90097-s.
32. Nishima W, Miyashita N, Yamaguchi Y, Sugita Y, Re S. Effect of bisecting GlcNAc and core fucosylation on conformational properties of biantennary complex-type N-glycans in solution. J Phys Chem B 2012; 116: 8504-12. doi:10.1021/jp212550z.
33. Stenqvist AC, Nagaeva O, Baranov V, Mincheva-Nilsson L. Exosomes secreted by human placenta carry functional Fas ligand and TRAIL molecules and convey apoptosis in activated immune cells, suggesting exosome-mediated immune privilege of the fetus. J Immunol 2013; 191: 5515-23. doi:10.4049/jimmunol.1301885.
34. Zhou Y, Fisher SJ, Janatpour M, et al. Human cytotrophoblasts adopt a vascular phenotype as they differentiate. A strategy for successful endovascular invasion? J Clin Invest 1997; 99: 2139- 51. doi:10.1172/jci119387.
35. Moser G, Gauster M, Orendi K, Glasner A, Theuerkauf R, Huppertz B. Endoglandular trophoblast, an alternative route of trophoblast invasion? Analysis with novel confrontation coculture models. Hum Reprod 2010; 25: 1127-36. doi:10.1093/ humrep/deq035.
36. Red-Horse K, Rivera J, Schanz A, et al. Cytotrophoblast induction of arterial apoptosis and lymphangiogenesis in an in vivo model of human placentation. J Clin Invest 2006; 116: 2643-52. doi:10.1172/jci27306.
37. Svensson-Arvelund J, Mehta RB, Lindau R, et al. The human fetal placenta promotes tolerance against the semiallogeneic fetus by inducing regulatory T cells and homeostatic M2 macrophages. J Immunol 2015; 194: 1534-44. doi:10.4049/ jimmunol.1401536.
38. Carosella ED, Rouas-Freiss N, Tronik-Le Roux D, Moreau P, LeMaoult J. HLA-G: An immune checkpoint molecule. Adv Immunol 2015; 127: 33-144. doi:10.1016/bs.ai.2015.04.001.
39. Fernandes SLE, de Carvalho FAG. Preimplantation genetic testing: A narrative review. Porto Biomed J 2024; 9: 262. doi:10.1097/j.pbj.000.000.0000000262.
40. Dinsmore J, Soriano P. MAPK and PI3K signaling: At the crossroads of neural crest development. Dev Biol 2018; 444 Suppl 1: S79-s97. doi:10.1016/j.ydbio.2018.02.003.
41. Cho DJ, Liang P. S-phase-coupled apoptosis in tumor suppression. Cell Mol Life Sci 2011; 68: 1883-96. doi:10.1007/ s00018.011.0666-x.
42. Ciarmela P, Islam MS, Reis FM, et al. Growth factors and myometrium: biological effects in uterine fibroid and possible clinical implications. Human Reproduction Update 2011; 17: 772-790. doi:10.1093/humupd/dmr031.
43. Liang L, Li Z, Ma T, et al. Transplantation of human placentaderived mesenchymal stem cells alleviates critical limb ischemia in diabetic nude rats. Cell Transplant 2017; 26: 45- 61. doi:10.3727/096368916x692726.
44. Barlow S, Brooke G, Chatterjee K, et al. Comparison of human placenta – and bone marrow-derived multipotent mesenchymal stem cells. Stem Cells Dev 2008; 17: 1095-107. doi:10.1089/scd.2007.0154.
45. Vacca P, Cantoni C, Prato C, et al. Regulatory role of NKp44, NKp46, DNAM-1 and NKG2D receptors in the interaction between NK cells and trophoblast cells. Evidence for divergent functional profiles of decidual versus peripheral NK cells. Int Immunol 2008; 20: 1395-405. doi:10.1093/intimm/dxn105.
46. DeJong CS, Maurice NJ, McCartney SA, Prlic M. Human tissue-resident memory T cells in the maternal-fetal interface. Lost Soldiers or Special Forces? Cells 2020; 9: doi:10.3390/ cells9122699.
47. Mjösberg J, Berg G, Jenmalm MC, Ernerudh J. FOXP3+ regulatory T cells and T helper 1, T helper 2, and T helper 17 cells in human early pregnancy decidua. Biol Reprod 2010; 82: 698-705. doi:10.1095/biolreprod.109.081208.
48. Schliefsteiner C, Ibesich S, Wadsack C. Placental Hofbauer cell polarization resists inflammatory cues in vitro. Int J Mol Sci 2020; 21: doi:10.3390/ijms21030736.
49. Brown MB, Chamier M, Allam AB, Reyes L. M1/M2 macrophage polarity in normal and complicated pregnancy. Front Immunol 2014; 5: 606. doi:10.3389/fimmu.2014.00606.
50. Zhu Y, Yang Y, Zhang Y, et al. Placental mesenchymal stem cells of fetal and maternal origins demonstrate different therapeutic potentials. Stem Cell Res Ther 2014; 5: 48. doi:10.1186/scrt436.
51. Bouland C, Philippart P, Dequanter D, et al. Cross-talk between mesenchymal stromal cells (MSCs) and endothelial progenitor cells (EPCs) in Bone Regeneration. Front Cell Dev Biol 2021; 9: 674084. doi:10.3389/fcell.2021.674084.
52. Jia Y, Ding X, Zhou L, Zhang L, Yang X. Mesenchymal stem cells-derived exosomal microRNA-139-5p restrains tumorigenesis in bladder cancer by targeting PRC1. Oncogene 2021; 40: 246-261. doi:10.1038/s41388.020.01486-7.
53. Rees JD, Wilson AM, Wolman RL. Current concepts in the management of tendon disorders. Rheumatology (Oxford) 2006; 45: 508-21. doi:10.1093/rheumatology/kel046.
54. Yang G, Rothrauff BB, Tuan RS. Tendon and ligament regeneration and repair: clinical relevance and developmental paradigm. Birth Defects Res C Embryo Today 2013; 99: 203- 222. doi:10.1002/bdrc.21041.
55. Ma R, Schär M, Chen T, et al. Use of human placenta-derived cells in a preclinical model of tendon injury. J Bone Joint Surg Am 2019; 101: e61. doi:10.2106/jbjs.15.01381.
56. Gwam C, Ohanele C, Hamby J, Chughtai N, Mufti Z, Ma X. Human placental extract: a potential therapeutic in treating osteoarthritis. Ann Transl Med 2023; 11: 322. doi:10.21037/ atm.2019.10.20.
57. S. Khalifeh Soltani, Forogh B, Ahmadbeigi N, et al. Safety and efficacy of allogenic placental mesenchymal stem cells for treating knee osteoarthritis: a pilot study. Cytotherapy 2019; 21: 54-63. doi:10.1016/j.jcyt.2018.11.003.
58. Dean RC, Lue TF. Physiology of penile erection and pathophysiology of erectile dysfunction. Urol Clin North Am 2005; 32: 379-95, v. doi:10.1016/j.ucl.2005.08.007.
59. Argiolas A, Argiolas M, Argiolas G, Melis MR. Erectile dysfunction: Treatments, advances and new therapeutic strategies. Brain Sci 2023; 13: doi:10.3390/brainsci13050802.
60. Lindsay MB, Schain DM, Grambsch P, Benson RC, Beard CM, Kurland LT. The incidence of Peyronie’s disease in Rochester, Minnesota, 1950 through 1984. J Urol 1991; 146: 1007-9. doi:10.1016/s0022-5347(17)37988-0.
61. Levy JA, Marchand M, Iorio L, Zribi G, Zahalsky MP. Effects of stem cell treatment in human patients with Peyronie Disease. J Am Osteopath Assoc 2015; 115: e8-13. doi:10.7556/ jaoa.2015.124.
62. Cho J, Kim TH, Seok J, et al. Vascular remodeling by placenta-derived mesenchymal stem cells restores ovarian function in ovariectomized rat model via the VEGF pathway. Laboratory Investigation 2021; 101: 304-317. doi:10.1038/ s41374.020.00513-1.
63. Kanelidis J, Premer C, Lopez J, Balkan W, Hare JM. Route of delivery modulates the efficacy of mesenchymal stem cell therapy for myocardial infarction. Circulation Research 2017; 120: 1139-1150. doi:10.1161/CIRCRESAHA.116.309819.
64. Shirbaghaee Z, Heidari Keshel S, Rasouli M, et al. Report of a phase 1 clinical trial for safety assessment of human placental mesenchymal stem cells therapy in patients with critical limb ischemia (CLI). Stem Cell Res Ther 2023; 14: 174. doi:10.1186/ s13287.023.03390-9.
65. Lan Y, Liu F, Chang L, et al. Combination of umbilical cord mesenchymal stem cells and standard immunosuppressive regimen for pediatric patients with severe aplastic anemia. BMC Pediatrics 2021; 21: 102. doi:10.1186/s12887.021.02562-x.
66. Shapiro AM, Lakey JR, Ryan EA, et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000; 343: 230-8. doi:10.1056/nejm200.007.273430401.
67. Musiał-Wysocka A, Kot M, Majka M. The pros and cons of mesenchymal stem cell-based therapies. Cell Transplant 2019; 28: 801-812. doi:10.1177/096.368.9719837897.
68. Chen LB, Jiang XB, Yang L. Differentiation of rat marrow mesenchymal stem cells into pancreatic islet beta-cells. World J Gastroenterol 2004; 10: 3016-20. doi:10.3748/wjg.v10. i20.3016.
69. Samikannu B, Chen C, Lingwal N, Padmasekar M, Engel FB, Linn T. Dipeptidyl peptidase IV inhibition activates CREB and improves islet vascularization through VEGF-A/VEGFR-2 signaling pathway. PLoS One 2013; 8: e82639. doi:10.1371/ journal.pone.0082639.
70. Jiang R, Han Z, Zhuo G, et al. Transplantation of placentaderived mesenchymal stem cells in type 2 diabetes: a pilot study. Front Med 2011; 5: 94-100. doi:10.1007/s11684.011.0116-z.
71. Gao S, Zhang Y, Liang K, Bi R, Du Y. Mesenchymal stem cells (MSCs): A novel therapy for type 2 diabetes. Stem Cells International 2022; 2022: 8637493. doi:10.1155/2022/8637493.
72. Hu L, Wang J, Zhou X, et al. Exosomes derived from human adipose mensenchymal stem cells accelerates cutaneous wound healing via optimizing the characteristics of fibroblasts. Sci Rep 2016; 6: 32993. doi:10.1038/srep32993.
73. Chen M, Chen X, Li X, et al. Subconjunctival administration of mesenchymal stem cells alleviates ocular inflammation in a murine model of corneal alkali burn. Stem Cells 2023; 41: 592- 602. doi:10.1093/stmcls/sxad027.
74. Philip KEJ, Lonergan B, Cumella A, Farrington-Douglas J, Laffan M, Hopkinson NS. COVID-19 related concerns of people with long-term respiratory conditions: a qualitative study. BMC Pulmonary Medicine 2020; 20: 319. doi:10.1186/ s12890.020.01363-9.
75. Harrell CR, Sadikot R, Pascual J, et al. Mesenchymal stem cell-based therapy of inflammatory lung diseases: Current understanding and future perspectives. Stem Cells Int 2019; 2019: 4236973. doi:10.1155/2019/4236973.
76. Kakabadze Z, Kipshidze N, Paresishvili T, Kipshidze N, Vadachkoria Z, Chakhunasvili D. Human placental mesenchymal stem cells for the treatment of ARDS in rat. Stem Cells Int 2022; 2022: 8418509. doi:10.1155/2022/8418509.
77. Chen K, Kolls JK. Innate lymphoid cells and acute respiratory distress syndrome. Am J Respir Crit Care Med 2016; 193: 350- 2. doi:10.1164/rccm.201.510.2101ED.
78. Hezam K, Wang C, Fu E, et al. Superior protective effects of PGE2 priming mesenchymal stem cells against LPSinduced acute lung injury (ALI) through macrophage immunomodulation. Stem Cell Research & Therapy 2023; 14: 48. doi:10.1186/s13287.023.03277-9.
79. Kim SY, Joglekar MV, Hardikar AA, et al. Placenta stem/ stromal cell-derived extracellular vesicles for potential use in lung repair. Proteomics 2019; 19: e1800166. doi:10.1002/ pmic.201800166.