Very Small Embryonic-Like Stem Cells A Review of Basic Science, Applications, and Potential Use in Orthopaedics

Main Article Content

Pierdanilo Sanna https://orcid.org/0000-0002-7431-8471
Loubna Abdel Hadi https://orcid.org/0000-0002-5271-0798
Rene Antonio Rivero-Jimenez https://orcid.org/0000-0001-7222-727X
Antonio Alfonso Bencomo-Hernandez https://orcid.org/0000-0002-6209-0393
Yasmine Maher Ahmed https://orcid.org/0000-0002-8918-0831
Gina Marcela Torres-Zambrano https://orcid.org/0000-0001-6424-2621
Yendry Ventura-Carmenate https://orcid.org/0000-0002-5373-3414

Keywords

Very Small Embryonic-like Stem Cells, VSELS, Pluripotent stem cells, Regenerative medicine, Orthopedic

Abstract

Continuous and growing research studies regarding the clinical applications of the pluripotent or multipo-tent stem cells with their potential to differentiate into three germ layers are very well conducted in regenerative medicine (RM). In this review, we report the recent clinical applications and potential use of very small embryonic-like stem cells (VSELs) in orthopedics. VSELs are nonhematopoietic (CD45 - / Lin -), rare, and very small cells; they were reported as “dormant” cells in the bone marrow (BM), but are also found in cord blood, peripheral blood (PB), and in adult organs. Based on their capability to express markers of pluripotency (such as Oct-4 +/Nanog +/SSEA-1/4+/CXCR4+), it has been hypothesized that these cells could be early deposited during the embryonic development as descendants of epiblast-derived stem cells and perhaps from some primordial germ cells. VSELs can be released or mobilized from the BM to the PB during tissue injury and stress, facilitating the regeneration of damaged tissues. As well as mesenchymal stem cells, nowadays VSELs can be expanded ex vivo. Their pluripotency could be suitable for applications in RM, solving several problems regarding the use of both controversial embryonic stem cells and induced pluripotent stem cells. VSELs studies will hopefully open new frontiers to better understand their potential that would be relevant for future applications in RM and translational research.

Abstract 710 | PDF Downloads 395

References

1. Berman L, Stulberg CS, Ruddle FH. Long-term tissue culture of human bone marrow. Report of isolation of a strain of cells resembling epithelial cells from bone marrow of a patient with carcinoma of the lung. Blood. 1955;10(9):896–911.
2. Mcculloch EA, Parker RC. Continuous cultivation of cells of hemic origin. Proc Can Cancer Conf. 1957; 2:152–67.
3. Friedenstein AJ, Chailakhjan RK, Lalykina KS. The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet. 1970;3(4):393–403. https://doi.org/10.1111/j.1365-2184.1970.tb00347.x
4. Caplan AI. Mesenchymal stem cells. J Orthop Res.1991;9(5):641–50. https://doi.org/10.1002/jor.1100090504
5. Horwitz EM, Le Blanc K, Dominici M, et al. Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement. Cytotherapy. 2005;7(5):393–5. https://doi.org/10.1080/14653240500319234
6. Caplan AI. Adult mesenchymal stem cells: When, where, and how. Stem Cells Int. 2015;2015: 628767. https://doi.org/10.1155/2015/628767
7. Caplan AI. Mesenchymal stem cells: Time to change the name! Stem Cells Transl Med. 2017;6(6):1445–51. https://doi.org/10.1002/sctm.17-0051
8. Kumar A, Ghosh Kadamb A, Ghosh Kadamb K. Mesenchymal or maintenance stem cell & understanding their role in osteoarthritis of the knee joint: A review article. Arch Bone Jt Surg. 2020;8(5):560–9. https://doi.org/10.22038/abjs.2020.42536.2155
9. Eggenhofer E, Benseler V, Kroemer A, et al. Mesenchymal stem cells are short-lived and do not migrate beyond the lungs after intravenous infusion. Front Immunol. 2012;3:297. https://doi.org/10.3389/fimmu.2012.00297
10. Haque N, Kasim NH, Rahman MT. Optimization of pre-transplantation conditions to enhance the efficacy of mesenchymal stem cells. Int J Biol Sci. 2015;11(3):324–34. https://doi.org/10.7150/ijbs.10567
11. Liu XB, Chen H, Chen HQ, et al. Angiopoietin-1 preconditioning enhances survival and functional recovery of mesenchymal stem cell transplantation. J Zhejiang Univ Sci B. 2012;13(8):616–23. https://doi.org/10.1631/jzus.B1201004
12. Satué M, Schüler C, Ginner N, Erben RG. Intra-articularly injected mesenchymal stem cells promote cartilage regeneration, but do not permanently engraft in distant organs. Sci Rep. 2019;9(1):10153. https://doi.org/10.1038/s41598-019-46554-5
13. García-Sánchez D, Fernández D, Rodríguez-Rey JC, Pérez-Campo FM. Enhancing survival, engraftment, and osteogenic potential of mesenchymal stem cells. World J Stem Cells. 2019;11(10):748–63. https://doi.org/10.4252/wjsc.v11.i10.748
14. Bhartiya D. Will iPS cells regenerate or just provide trophic support to the diseased tissues? Stem Cell Rev. 2018;14:629–31. https://doi.org/10.1007/s12015-018-9837-6
15. Kanji S, Pompili VJ, Das H. Plasticity and maintenance of hematopoietic stem cells during development. Recent Pat Biotechnol. 2011;5(1):40–53. https://doi.org/10.2174/187220811795655896
16. Alison MR, Poulsom R, Jeffery R, et al. Hepatocytes from non-hepatic adult stem cells. Nature. 2000;406(6793):257. https://doi.org/10.1038/35018642
17. Petersen BE, Bowen WC, Patrene KD, et al. Bone marrow as a potential source of hepatic oval cells. Science. 1999;284(5417):1168–70. https://doi.org/10.1126/science.284.5417.1168
18. Ferrari G, Cusella-De Angelis G, Coletta M, et al. Muscle regeneration by bone marrow-derived myogenic progenitors [published correction appears in Science. 1998;281(5379):923]. Science. 1998;279(5356):1528–30.
19. Gussoni E, Soneoka Y, Strickland CD, et al. Dystrophin expression in the mdx mouse restored by stem cell transplantation. Nature. 1999;401(6751):390–4. https://doi.org/10.1038/43919
20. Saw KY, Anz A, Siew-Yoke Jee C, et al. Articular cartilage regeneration with autologous peripheral blood stem cells versus hyaluronic acid: A randomized controlled trial. Arthroscopy. 2013;29(4):684–94. https://doi.org/10.1016/j.arthro.2012.12.008
21. Mezey E, Chandross KJ, Harta G, Maki RA, McKercher SR. Turning blood into brain: Cells bearing neuronal antigens generated in vivo from bone marrow. Science. 2000;290:1779–82. https://doi.org/10.1126/science.290.5497.1779
22. Brazelton TR, Rossi FM, Keshet GI, Blau HM. From marrow to brain: Expression of neuronal phenotypes in adult mice. Science. 2000;290:1775–9. https://doi.org/10.1126/science.290.5497.1775
23. Asahara T, Masuda H, Takahashi T, et al. Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res. 1999;85(3):221–8. https://doi.org/10.1161/01.res.85.3.221
24. Bittner RE, Schöfer C, Weipoltshammer K, et al. Recruitment of bone-marrow-derived cells by skeletal and cardiac muscle in adult dystrophic mdx mice. Anat Embryol (Berl). 1999;199(5):391–6. https://doi.org/10.1007/s004290050237
25. Orlic D, Kajstura J, Chimenti S, Bodine DM, Leri A, Anversa P. Transplanted adult bone marrow cells repair myocardial infarcts in mice. Ann N Y Acad Sci. 2001;938:221–9. https://doi.org/10.1111/j.1749-6632.2001.tb03592.x
26. Kucia M, Reca R, Campbell FR, et al. A population of very small embryonic-like (VSEL) CXCR4(+) SSEA-1(+) Oct-4+ stem cells identified in adult bone marrow. Leukemia. 2006;20(5):857–69. https://doi.org/10.1038/sj.leu.2404171
27. Bhartiya D. Pluripotent stem cells in adult tissues: Struggling to be acknowledged over two decades. Stem Cell Rev. 2017;13:713–24. https://doi.org/10.1007/s12015-017-9756-y
28. Kucia M, Reca R, Jala VR, Dawn B, Ratajczak J, Ratajczak MZ. Bone marrow as a home of heterogenous populations of nonhematopoietic stem cells. Leukemia. 2005;19(7):1118–27. https://doi.org/10.1038/sj.leu.2403796
29. Eglitis MA, Mezey E. Hematopoietic cells differentiate into both microglia and macroglia in the brains of adult mice. Proc Natl Acad Sci U S A. 1997;94(8):4080–5. https://doi.org/10.1073/pnas.94.8.4080
30. Kucia M, Wu W, Ratajczak MZ. Bone marrow-derived very small embryonic-like stem cells: Their developmental origin and biological significance. Dev Dyn. 2007;236(12):3309–20. https://doi.org/10.1002/dvdy.21180
31. Kmiecik TE, Keller JR, Rosen E, Vande Woude GF. Hepatocyte growth factor is a synergistic factor for the growth of hematopoietic progenitor cells. Blood. 1992;80(10):2454–7.
32. Nagasawa T. A chemokine, SDF-1/PBSF, and its receptor, CXC chemokine receptor 4, as mediators of hematopoiesis. Int J Hematol. 2000;72(4):408–11.
33. Taichman R, Reilly M, Verma R, Ehrenman K, Emerson S. Hepatocyte growth factor is secreted by osteoblasts and cooperatively permits the survival of haematopoietic progenitors. Br J Haematol. 2001;112(2):438–48. https://doi.org/10.1046/j.1365-2141.2001.02568.x
34. Shin DM, Suszynska M, Mierzejewska K, Ratajczak J, Ratajczak MZ. Very small embryonic-like stem-cell optimization of isolation protocols: An update of molecular signatures and a review of current in vivo applications. Exp Mol Med. 2013;45(11):e56. https://doi.org/10.1038/emm.2013.117
35. Kucia M, Halasa M, Wysoczynski M, et al. Morphological and molecular characterization of novel population of CXCR4+ SSEA-4+ Oct-4+ very small embryonic-like cells purified from human cord blood: Preliminary report. Leukemia. 2007;21(2):297–303. https://doi.org/10.1038/sj.leu.2404470
36. Bhartiya D, Shaikh A, Anand S, et al. Endogenous, very small embryonic-like stem cells: Critical review, therapeutic potential and a look ahead. Hum Reprod Update. 2016;23(1):41–76. https://doi.org/10.1093/humupd/dmw030
37. Kucia M, Machalinski B, Ratajczak MZ. The developmental deposition of epiblast/germ cell-line derived cells in various organs as a hypothetical explanation of stem cell plasticity? Acta Neurobiol Exp (Wars). 2006;66(4):331–41.
38. Ratajczak MZ, Machalinski B, Wojakowski W, Ratajczak J, Kucia M. A hypothesis for an embryonic origin of pluripotent Oct-4(+) stem cells in adult bone marrow and other tissues. Leukemia. 2007;21(5):860–7. https://doi.org/10.1038/sj.leu.2404630
39. Abdel-Latif A, Zuba-Surma EK, Ziada KM, et al. Evidence of mobilization of pluripotent stem cells into peripheral blood of patients with myocardial ischemia. Exp Hematol. 2010;38(12):1131–42.e1. https://doi.org/10.1016/j.exphem.2010.08.003
40. Borlongan CV, Glover LE, Tajiri N, Kaneko Y, Freeman TB. The great migration of bone marrow-derived stem cells toward the ischemic brain: Therapeutic implications for stroke and other neurological disorders. Prog Neurobiol. 2011;95(2):213–28. https://doi.org/10.1016/j.pneurobio.2011.08.005
41. Grymula K, Tarnowski M, Piotrowska K, et al. Evidence that the population of quiescent bone marrow-residing very small embryonic/epiblast-like stem cells (VSELs) expands in response to neurotoxic treatment. J Cell Mol Med. 2014;18(9):1797–806. https://doi.org/10.1111/jcmm.12315
42. Guerin CL, Loyer X, Vilar J, et al. Bone-marrow-derived very small embryonic-like stem cells in patients with critical leg ischaemia: Evidence of vasculogenic potential. Thromb Haemost. 2015;113(5):1084–94. https://doi.org/10.1160/TH14-09-0748
43. Guerin CL, Blandinières A, Planquette B, et al. Very small embryonic-like stem cells are mobilized in human peripheral blood during hypoxemic COPD exacerbations and pulmonary hypertension. Stem Cell Rev Rep. 2017;13(4):561–6. https://doi.org/10.1007/s12015-017-9732-6
44. Prockop DJ. Marrow stromal cells as stem cells for nonhematopoietic tissues. Science. 1997;276(5309):71–4. https://doi.org/10.1126/science.276.5309.71
45. Jiang Y, Jahagirdar BN, Reinhardt RL, et al. Pluripotency of mesenchymal stem cells derived from adult marrow [published correction appears in Nature. 2007;447(7146):879–80]. Nature. 2002;418(6893):41–9.
46. D’Ippolito G, Diabira S, Howard GA, Menei P, Roos BA, Schiller PC. Marrow-isolated adult multilineage inducible (MIAMI) cells, a unique population of postnatal young and old human cells with extensive expansion and differentiation potential. J Cell Sci. 2004;117(Pt 14):2971–81. https://doi.org/10.1242/jcs.01103
47. Heneidi S, Simerman AA, Keller E, et al. Awakened by cellular stress: Isolation and characterization of a novel population of pluripotent stem cells derived from human adipose tissue [published correction appears in PLoS One. 2013;8(7). PLoS One. 2013;8(6):e64752. https://doi.org/10.1371/journal.pone.0064752
48. Kuroda Y, Kitada M, Wakao S, et al. Unique multipotent cells in adult human mesenchymal cell populations. Proc Natl Acad Sci U S A. 2010;107(19):8639–43. https://doi.org/10.1073/pnas.0911647107
49. Bhartiya D, Patel H, Ganguly R, et al. Novel insights into adult and cancer stem cell biology. Stem Cells Dev. 2018;27(22):1527–39. https://doi.org/10.1089/scd.2018.0118
50. Lahlil R, Scrofani M, Barbet R, Tancredi C, Aries A, Hénon P. VSELs maintain their pluripotency and competence to differentiate after enhanced ex vivo expansion. Stem Cell Rev Rep. 2018;14(4):510–24. https://doi.org/10.1007/s12015-018-9821-1
51. de Lima M, McNiece I, Robinson SN, et al. Cord-blood engraftment with ex vivo mesenchymal-cell coculture. N Engl J Med. 2012;367(24):2305–15. https://doi.org/10.1056/NEJMoa1207285
52. Boitano AE, Wang J, Romeo R, et al. Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells [published correction appears in Science. 2011 May 6;332(6030):664]. Science. 2010;329(5997):1345–8.
53. Lahlil R, Scrofani M, Barbet R, Tancredi C, Aries A, Hénon P. VSELs maintain their pluripotency and competence to differentiate after enhanced ex vivo expansion. Stem Cell Rev Rep. 2018 Aug;14(4):510-524. doi: 10.1007/s12015-018-9821-1. PMID: 29736843; PMCID: PMC6013546.

54. Shin DM, Liu R, Wu W, et al. Global gene expression analysis of very small embryonic-like stem cells reveals that the Ezh2-dependent bivalent domain mechanism contributes to their pluripotent state. Stem Cells Dev. 2012;21(10):1639–52. https://doi.org/10.1089/scd.2011.0389
55. Shin DM, Zuba-Surma EK, Wu W, et al. Novel epigenetic mechanisms that control pluripotency and quiescence of adult bone marrow-derived Oct4(+) very small embryonic-like stem cells. Leukemia. 2009;23(11):2042–51. https://doi.org/10.1038/leu.2009.153
56. Alvarez-Gonzalez C, Duggleby R, Vagaska B, et al. Cord blood Lin(-) CD45(-) embryonic-like stem cells are a heterogeneous population that lack self-renewal capacity. PLoS One. 2013;8(6):e67968. https://doi.org/10.1371/journal.pone.0067968
57. Ratajczak J, Wysoczynski M, Zuba-Surma E, et al. Adult murine bone marrow-derived very small embryonic-like stem cells differentiate into the hematopoietic lineage after coculture over OP9 stromal cells. Exp Hematol. 2011;39(2):225–37. https://doi.org/10.1016/j.exphem.2010.10.007
58. Shin DM, Liu R, Klich I, Ratajczak J, Kucia M, Ratajczak MZ. Molecular characterization of isolated from murine adult tissues very small embryonic/epiblast like stem cells (VSELs). Mol Cells. 2010;29(6):533–8. https://doi.org/10.1007/s10059-010-0081-4
59. Shin DM, Liu R, Klich I, et al. Molecular signature of adult bone marrow-purified very small embryonic-like stem cells supports their developmental epiblast/germ line origin. Leukemia. 2010;24(8):1450–61. https://doi.org/10.1038/leu.2010.121
60. Mierzejewska K, Heo J, Kang JW, et al. Genome-wide analysis of murine bone marrow derived very small embryonic-like stem cells reveals that mitogenic growth factor signaling pathways play a crucial role in the quiescence and ageing of these cells. Int J Mol Med. 2013;32(2):281–90. https://doi.org/10.3892/ijmm.2013.1389
61. Ratajczak MZ, Zuba-Surma EK, Shin DM, Ratajczak J, Kucia M. Very small embryonic-like (VSEL) stem cells in adult organs and their potential role in rejuvenation of tissues and longevity. Exp Gerontol. 2008;43(11):1009–17. https://doi.org/10.1016/j.exger.2008.06.002
62. Havens AM, Shiozawa Y, Jung Y, et al. Human very small embryonic-like cells generate skeletal structures, in vivo. Stem Cells Dev. 2013;22(4):622–30. https://doi.org/10.1089/scd.2012.0327
63. Leppik L, Sielatycka K, Henrich D, et al. Role of adult tissue-derived pluripotent stem cells in bone regeneration. Stem Cell Rev Rep. 2020;16(1):198–211. https://doi.org/10.1007/s12015-019-09943-x
64. Teitelbaum SL. Stem cells and osteoporosis therapy. Cell Stem Cell. 2010;7(5):553–4. https://doi.org/10.1016/j.stem.2010.10.004
65. Li X, Zhou ZY, Zhang YY, Yang HL. IL-6 contributes to the defective osteogenesis of bone marrow stromal cells from the vertebral body of the glucocorticoid-induced osteoporotic mouse. PLoS One. 2016;11(4):e0154677. https://doi.org/10.1371/journal.pone.0154677
66. Itkin T, Kaufmann KB, Gur-Cohen S, Ludin A, Lapidot T. Fibroblast growth factor signaling promotes physiological bone remodeling and stem cell self-renewal. Curr Opin Hematol. 2013;20(3):237–44. https://doi.org/10.1097/MOH.0b013e3283606162
67. Vicari L, Calabrese G, Forte S, et al. Potential role of activating transcription factor 5 during osteogenesis. Stem Cells Int. 2016;2016:5282185. https://doi.org/10.1155/2016/5282185
68. Bionaz M, Monaco E, Wheeler MB. Transcription adaptation during in vitro adipogenesis and osteogenesis of porcine mesenchymal stem cells: Dynamics of pathways, biological processes, up-stream regulators, and gene networks. PLoS One. 2015;10(9):e0137644. https://doi.org/10.1371/journal.pone.0137644
69. Yang M, Li CJ, Sun X, et al. MiR-497∼195 cluster regulates angiogenesis during coupling with osteogenesis by maintaining endothelial Notch and HIF-1α activity. Nat Commun. 2017;8:16003. https://doi.org/10.1038/ncomms16003
70. Younghun J. Efficacy of human VSELs to reverse bone loss in osteoporosis. J Dent Res (Spec Issue: 2015 IADR/AADR/CADR General Session (Boston, Massachusetts): Abstract number 1757. Available from: https://iadr.abstractarchives.com/abstract/15iags-2107101/efficacy-of-human-vsels-to-reverse-bone-loss-in-osteoporosis
71. Catacchio I, Berardi S, Reale A, et al. Evidence for bone marrow adult stem cell plasticity: Properties, molecular mechanisms, negative aspects, and clinical applications of hematopoietic and mesenchymal stem cells transdifferentiation. Stem Cells Int. 2013;2013:589139. https://doi.org/10.1155/2013/589139