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Wharton’s Jelly Mesenchymal Stromal Cells as a Feeder Layer for the Ex Vivo Expansion of Hematopoietic Stem and Progenitor Cells: a Review

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Abstract

In recent years, umbilical cord blood (UCB) has been widely used as an alternative source to bone marrow (BM) for transplantation of hematopoietic stem and progenitor cells (HSPCs) in a variety of hematological and non-hematological disorders. Nevertheless, the insufficient number of UCB-HSPCs for graft represents a major challenge. HSPCs ex vivo expansion prior to transplantation is a valid strategy to overcome this limit. Several attempts to optimize the expansion conditions have been reported, including the use of mesenchymal stromal cells (MSCs) as feeder layer. Wharton’s Jelly (WJ), the main component of umbilical cord (UC) matrix, is especially rich in MSCs, which are considered ideal candidates for feeder layer in co-culture systems. In fact, they can be easily harvested and grow robustly in culture, producing a confluent monolayer in a short time. Similarly to bone marrow-mesenchymal stromal cells (BM-MSCs), WJ-derived MSCs (WJ-MSCs) have been used to support hematopoiesis in vitro and in vivo. Here, we review the rationale for using MSCs, particularly WJ-MSCs, as a feeder layer for UCB-HSPCs ex vivo expansion. In addition, we report the main findings attesting the use of these MSCs as a support in hematopoiesis.

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References

  1. Cohen, Y., & Nagler, A. (2004). Umbilical cord blood transplantation-how, when and for whom? Blood Reviews, 18(3), 167–179.

    Article  PubMed  Google Scholar 

  2. Mayani, H., & Lansdorp, P. M. (1998). Biology of human umbilical cord blood derived hematopoietic stem/progenitor cells. Stem Cells, 16, 153–165.

    Article  CAS  PubMed  Google Scholar 

  3. Kita, K., Lee, J. O., Finnerty, C. C., & Herndon (2011). Cord blood-derived hematopoietic stem/progenitor. Cells: Current challenges in Engraftment, Infection, and Ex vivo expansion. Stem cells International. doi:10.4061/2011/276193.

    Google Scholar 

  4. Zhang, Y., Chai, C., Jiang, X. S., Teoh, S. H., & Leong, K. W. (2006). Co-culture of umbilical cord blood CD34+ cells with human mesenchymal stem cells. Tissue Engineering, 12, 2161–2170.

    Article  PubMed  Google Scholar 

  5. Robinson, S. N., Simmons, P. J., Yang, H., Alousi, A. M., de Lima, J. M., & Shpall, E. J. (2011). Mesenchymal stem cells in ex vivo cord blood expansion. Best Practice & Research. Clinical Haematology, 24, 83–92.

    Article  CAS  Google Scholar 

  6. Troyer, D. L., & Weiss, M. L. (2007). Concise review: Wharton’s jelly-derived cells are a primitive stromal cell population. Stem Cells, 26, 591–599.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Corrao, S., La Rocca, G., Lo Iacono, M., Corsello, T., Farina, F., & Anzalone, R. (2013). Umbilical cord revisited: from Wharton’s jelly myofibroblasts to mesenchymal stem cells. Histology and Histopathology, 28, 1235–1244.

    PubMed  Google Scholar 

  8. Anzalone, R., Farina, F., Zummo, G., & La Rocca, G. (2011). Recent patents and advances on isolation and cellular therapy applications of mesenchymal stem cells from human umbilical cord Wharton’s jelly. Recent Patents on Regenerative Medicine, 1, 216–227.

  9. D’Arena, G., Musto, P., Cascavilla, N., et al. (1996). Human umbilical cord blood: immunophenotypic Heterogeity of CD34 + hematopoietic progenitor cells. Hematologica, 81, 404–409.

    Google Scholar 

  10. Civin, C. I., & Gore, S. D. (1993). Antigenic analysis of hematopoiesis: a review. Journal of Hematotherapy, 2, 137–144.

    Article  CAS  PubMed  Google Scholar 

  11. Piacibello, W., Sanavio, F., & Garetto, L. (1997). Extensive amplification and self-renewal of human primitive hematopoietic stem cells from cord blood. Blood, 89(8), 2644–2653.

    CAS  PubMed  Google Scholar 

  12. Chotinantakul, K., Prasajak, P., & Leeanansaksiri, W. (2013). Wnt1 accelerates an ex vivo expansion of human cord blood CD34(+)CD38(-) cells. Stem Cells International, 2013, 909812. doi:10.1155/2013/909812 .Epub 2013 Aug 20

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Mosaad, Y. M. (2014). Hematopoietic stem cells: an overview. Transfusion and Apheresis Science, 51, 68–82.

    Article  PubMed  Google Scholar 

  14. Wynter, E. A., Emmerson, A. J. B., & Testa, N. G. (1999). Properties of peripheral blood and cord blood stem cells. Bailliere’s Clinical Hematology, 12, 1–17.

    Google Scholar 

  15. Leung, W., Ramirez, M., Novelli, E. M., et al. (1998). In vivo engraftment potential of clinical hematopoietic grafts. Journal of Investigative Medicine, 46(6), 303–311.

    CAS  PubMed  Google Scholar 

  16. Lewis, I., & Verfaillie, C. M. (2000). Multi-lineage expansion potential of primitive hematopoietic progenitors. Superiority of umbilical cord blood compared to mobilized peripheral blood. Experimental Hematology, 28(9), 1087–1095.

    Article  CAS  PubMed  Google Scholar 

  17. Aldenhoven, M., & Kurtzberg, J. (2015). Cord blood is the optimal graft source for the treatment of pediatric patients with lysosomal storage diseases: clinical outcomes and future directions. Cytotherapy, 17(6), 765–774. doi:10.1016/j.jcyt.2015.03.609 .Epub 2015 Mar 31

    Article  CAS  PubMed  Google Scholar 

  18. Dominici, M., Le Blanc, K., Mueller, I., et al. (2006). Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy, 8, 315–317.

    CAS  PubMed  Google Scholar 

  19. Huang, Y. C., Parolini, O., La Rocca, G., & Deng, L. (2012). Umbilical cord versus bone marrow-derived mesenchymal stromal cells. Stem Cells and Development, 21, 2900–2903.

    Article  CAS  PubMed  Google Scholar 

  20. La Rocca, G., Anzalone, R., Corrao, S., et al. (2009). Isolation and characterization of Oct-4+/HLA-G+ mesenchymal stem cells from human umbilical cord matrix: differentiation potential and detection of new markers. Histochemistry and Cell Biology, 131, 267–282.

    Article  CAS  PubMed  Google Scholar 

  21. Batsali, A. K., Kastrinaki, M. C., Papadaki, H. A., & Pontikoglou, C. (2013). Mesenchymal stem cells derived from Wharton’s jelly of the umbilical cord: biological properties and emerging clinical applications. Current Stem Cell Research & Therapy, 8, 144–155.

    Article  CAS  Google Scholar 

  22. Anzalone, R., Lo Iacono, M., Loria, T., et al. (2011). Wharton’s jelly mesenchymal stem cells as candidates for beta cells regeneration: extending the differentiative and immunomodulatory benefits of adult mesenchymal stem cells for the treatment of type 1 diabetes. Stem Cell Reviews and Reports, 7, 342–363.

    Article  PubMed  Google Scholar 

  23. Lo Iacono, M., Anzalone, R., Corrao, S., et al. (2011). Perinatal and Wharton’s jelly derived mesenchymal stem cells in cartilage regenerative medicine and tissue engineering strategies. The Open Tissue Engineering and Regenerative Medicine Journal, 4, 72–81.

    Article  CAS  Google Scholar 

  24. Corrao, S., La Rocca, G., Lo Iacono, M., et al. (2013). New frontiers in regenerative medicine in cardiology: the potential of Wharton’s jelly mesenchymal stem cells. Current Stem Cell Research & Therapy, 8, 39–45.

    Article  CAS  Google Scholar 

  25. Anzalone, R., Farina, F., Zummo, G., & La Rocca, G. (2011). Recent patents and advances on isolation and cellular therapy applications of mesenchymal stem cells from human umbilical cord Wharton’s jelly. Recent Patents on Regenerative Medicine, 1, 216–227.

  26. De Bruyn, C., Najar, M., Raicevic, G., et al. (2011). A rapid, simple, and reproducible method for the isolation of mesenchymal stromal cells from Wharton’s jelly without enzymatic treatment. Stem Cells and Development, 20, 547–557.

    Article  CAS  PubMed  Google Scholar 

  27. Anzalone, R., Lo Iacono, M., Corrao, S., et al. (2010). New emerging potentials for human Wharton’s jelly mesenchymal stem cells: immunological features and hepatocyte-like differentiative capacity. Stem Cells and Development, 19(4), 423–437.

    Article  CAS  PubMed  Google Scholar 

  28. Weiss, M. L., Medicetty, S., Bledsoe, A. R., et al. (2006). Human umbilical cord matrix stem cells: preliminary characterization and effect of transplantation in a rodent model of Parkinson’s disease. Stem Cells, 24, 781–792.

    Article  CAS  PubMed  Google Scholar 

  29. Anzalone, R., Corrao, S., Lo Iacono, M., et al. (2013). Isolation and characterization of CD276+/HLA-E+ human subendocardial mesenchymal stem cells from chronic heart failure patients: analysis of differentiative potential and immunomodulatory markers expression. Stem Cells and Development, 22, 1–17.

    Article  CAS  PubMed  Google Scholar 

  30. Karahuseyinoglu, S., Cinar, O., Kilic, E., et al. (2007). Biology of stem cells in human umbilical cord stroma: in situ and in vitro surveys. Stem Cells, 25, 319–331.

    Article  CAS  PubMed  Google Scholar 

  31. Tondreau, T., Lagneaux, L., Dejeneffe, M., et al. (2004). Bone marrow-derived mesenchymal stem cells already express specifi c neural proteins before any differentiation. Differentiation, 72, 319–326.

    Article  CAS  PubMed  Google Scholar 

  32. Hung, S. C., Chen, N. J., Li, H.-S., Ma, H.-L., & Lo, W.-H. (2002). Isolation and characterization of size-sieved stem cells from human bone marrow. Stem Cells, 20, 249–258.

    Article  PubMed  Google Scholar 

  33. Turnovcova, K., Ruzickova, K., Vanecek, V., Sykova, E., & Jendelova, P. (2009). Properties and growth of human bone marrow mesenchymal stromal cells cultivated in different media. Cytotherapy, 25, 1–12.

    Article  Google Scholar 

  34. Karaoz, E., Aksoy, A., Ayhan, S., Sarıboyacı, A. E., Kaymaz, F., & Kasap, M. (2009). Characterization of mesenchymal stem cells from rat bone marrow: ultrastructural properties, differentiation potential and immunophenotypic markers. Histochemistry and Cell Biology, 132, 533–546.

    Article  CAS  PubMed  Google Scholar 

  35. Nilsson, S. K., Johnston, H. M., Whitty, G. A., et al. (2005). Osteopontin, a key component of the hematopoietic stem cell niche and regulator of primitive hematopoietic progenitor cells. Blood, 106, 1232–1239.

    Article  CAS  PubMed  Google Scholar 

  36. Raio, L., Cromi, A., Ghezzi, F., et al. (2005). Hyaluronic content of wharton’s jelly in healthy and down syndrome foetuses. Matrix Biology, 2005(24), 166–174.

    Article  CAS  Google Scholar 

  37. Li, Tian, and Wu, Y. (2001). Paracrine molecules of mesenchymal stem cells for hematopoietic stem cell niche. Bone marrow research, ID353878, 8 doi:10.1155/2011/353878.

  38. Mishima, S., Nagai, A., & Abdullah, S. (2010). Effective ex vivo expansion of hematopoietic stem cells using osteoblast-differentiated mesenchymal stem cells is CXCL12 dependent. European Journal of Haematology, 84(6), 538–546.

    Article  CAS  PubMed  Google Scholar 

  39. Sugiyama, T., Kohara, H., Noda, M., & Nagasawa, T. (2006). Maintenance of hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity, 25(6), 977–988.

    Article  CAS  PubMed  Google Scholar 

  40. Lu, L. L., Liu, Y. J., & Yang, S. G. (2006). Isolation and characterization of human umbilical cord mesenchymal stem cells with hematopoiesis-supportive function and other potentials. Haematologica, 91(8), 1017–1026.

    CAS  PubMed  Google Scholar 

  41. Friedman, R., Betancur, M., Boissel, L., Tuncer, H., Cetrulo, C., Klingermann, H. (2007). Umbilical Cord mesenchymal Stem Cells: Adjuvants for Human Cell Transplantation, 13, 1477–1486.

  42. Ke, Z., & Liu, Q. (2016). The clinical application of mesenchymal stromal cells in hematopoietic stem cell transplantation. Journal of Hematology & Oncology, 9, 46.

    Article  Google Scholar 

  43. Alma, J., Nauta, W., & Fibbe, E. (2007). Immunomodulatory properties of mesenchymal stromal cells. Blood, 110, 3499–3506.

    Article  CAS  Google Scholar 

  44. Aggarwal, S., & Pittenger, M. F. (2005). Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood, 105, 1815–1818.

    Article  CAS  PubMed  Google Scholar 

  45. Chan, C. K., Wu, K. H., Lee, Y. S., et al. (2012). The comparison of interleukin-6-associated immunosuppressive effect of human ESCs, fetal type-MSCs, and adult-type MSCs. Transplantation, 94, 132.

    Article  PubMed  Google Scholar 

  46. La Rocca, G., Corrao, S., Lo Iacono, M., Corsello, T., Farina, F., & Anzalone, R. (2012). Novel immunomodulatory markers expressed by human WJ-MSC: an updated review in regenerative and reparative medicine. The Open Tissue Engineering and Regenerative Medicine Journal, 5, 50–58.

    Article  CAS  Google Scholar 

  47. Corrao, S., Campanella, C., Anzalone, R., et al. (2010). Human Hsp10 and early pregnancy factor (EPF) and their relationship and involvement in cancer and immunity: current knowledge and perspectives. Life Sciences, 86, 145–152.

    Article  CAS  PubMed  Google Scholar 

  48. Corrao, S., Anzalone, R., Lo Iacono, M., et al. (2014). Hsp10 nuclear localization and changes in lung cells response to cigarette smoke suggest novel roles for this chaperonin. Open Biology, 4(10). doi:10.1098/rsob.140125.

  49. Fanchin, R., Galiot, V., Rouas-Freiss, N., Frydman, R., & Carosella, E. D. (2009). Implication of HLA-G in human embryo implantation. Human Immunology, 68, 259–263.

    Article  CAS  Google Scholar 

  50. Weiss, M. L., Anderson, C., Medicetty, S., et al. (2008). Immune properties of human umbilical cord Wharton’s jelly-derived cell. Stem Cells, 26, 2865–2874.

    Article  CAS  PubMed  Google Scholar 

  51. Valencic, E., Piscianz, E., Andolina, A., Ventura, A., & Tommasini, A. (2010). The immunosuppressive effect of Wharton’s jelly sromal cells depends on the timing of their licensing and on lymphocyte activation. Cytotherapy, 12, 154–160.

    Article  CAS  PubMed  Google Scholar 

  52. Tipnis, S., Viswanathan, C., & Majumdar, A. S. (2010). Immunosuppressive properties of human umbilical cord derived mesenchymal stem cells: role of B7-H1 and IDO. Immunology and Cell Biology, 88, 795–806.

    Article  PubMed  Google Scholar 

  53. Gluckman, E. (2000). Current status of umbilical cord blood hematopoietic stem cell transplantation. Experimental Hematology, 28, 1197–1205.

    Article  CAS  PubMed  Google Scholar 

  54. Broxmeyer, H. E. (2010). Umbilical cord transplantation: epilogue. Seminars in Hematology, 3, 272–283.

    Google Scholar 

  55. Ballen, K., Gluckman, E., & Broxmeyer, H. E. (2013). Umbilical cord blood transplantation: the first 25 years and beyond. Blood, 122, 491–498.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Gluckman, E., Rocha, V., Arcese, W., et al. (2004). Factors associated with outcomes of unrelated cord blood transplant: guidelines for donor choice. Experimental Hematology, 32(4), 397–407.

    Article  CAS  PubMed  Google Scholar 

  57. Brown, J., & Boussiotis, V. A. (2009). Umbilical cord blood transplantation: basic biology and clinical challenges to immune reconstitution. Clinical Immunology 2008, 127(3), 286–297. doi:10.1016/j.clim.2008.02.008.

    Google Scholar 

  58. Gluckman, E., Rocha, V., Boyer-Chammard, A., et al. (1997). Outcome of cord-blood transplantation from related and unrelated donors. Eurocord transplant group and the European blood and marrow transplantation group. New England Journal of Medicine, 337, 373–381.

    Article  CAS  PubMed  Google Scholar 

  59. Norkin, M, Lazarus, H.M., Wingard, J.R. (2013). Umbilical cord blood graft enhancement strategies: has the time come to move these into the clinic?. Bone Marrow Transplantation 48, 884–889.

  60. Sideri, A., Neokleous, N., De La Brunet Grange, P., et al. (2011). An overview of the progress on double umbilical cord blood transplantation. Haematologica, 96, 1213–1220.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Barker, J. N., Weisdorf, D. J., De For, T. E., et al. (2005). Transplantation of 2 partially HLA-matched umbilical cord blood units to enhance engraftment in adults with hematologic malignancy. Blood, 105, 1343–1347.

    Article  CAS  PubMed  Google Scholar 

  62. Dahlberg, A., Delaney, C., & Bernstein, I. D. (2011). Ex vivo expansion of human hematopoietic stem and progenitor cells. Blood, 117, 6083–6090.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Bari, S., Seah, K. K., Poon, Z., et al. (2015). Expansion and homing of umbilical cord blood hematopoietic stem and progenitor cells for clinical transplantation. Biology of Blood and Marrow Transplantation, 21, 1008–1019.

    Article  PubMed  Google Scholar 

  64. Shpall, E. J., Quinones, R., Giller, R., et al. (2002). Transplantation of ex vivo expanded cord blood. Biology of Blood and Marrow Transplantation, 8(7), 368–376.

    Article  PubMed  Google Scholar 

  65. de Lima, M., Mc Mannis J.D., Saliba, R., et al. (2008). Double cord blood transplantation (CBT) with and without ex-vivo expansion (EXP): a randomized, controlled study [abstract]. Blood, 112 Abstract 154.

  66. Jaroscak, J., Goltry, K., Smith, A., et al. (2003). Augmentation of umbilical cord blood (UCB) transplantation with ex vivo-expanded UCB cells: results of a phase I trial using the Aastrom Replicell system. Blood, 101(12), 5061–5067.

    Article  CAS  PubMed  Google Scholar 

  67. Zhang, C. C., Kaba, M., Ge, G., et al. (2006). Angiopoietin-like proteins stimulate ex vivo expansion of hematopoietic stem cells. Nature Medicine, 12, 240–245.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Himburg, H. A., Muramoto, G. G., Daher, P., et al. (2010). Pleiotrophin regulates the expansion and re generation of hematopoietic stem cells. Nature Medicine, 16, 475–482.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Celebi, B., Mantovan, D., & Pineault, N. (2012). Insulin-like growth factor binding protein-2 and neurotrophin 3 synergize together to promote the expansion of hematopoietic cells ex vivo. Cytokine, 58, 327–331.

    Article  CAS  PubMed  Google Scholar 

  70. Ventura, F. M. S., Labude, N., Walenda, G., et al. (2013). Ex vivo expansion of cord blood-cd34(+) cells using IGFBP2 and Angptl-5 impairs short-term lymphoid repopulation in vivo. Journal of Tissue Engineering and Regenerative Medicine, 7, 944–954.

    Article  CAS  Google Scholar 

  71. Zhang, Y., & Gao, Y. (2016). Novel chemical attempts at ex vivo hematopoietic stem cell expansion. International Journal of Hematology, 103(5), 519–529. doi:10.1007/s12185-016-1962-x.

  72. De Lima, M., McMannis, J., Gee, A., et al. (2008). Transplantation of ex vivo expanded cord blood cells using the copper chelator tetraethylene-pentamine: a phase I/II clinical trial. Bone Marrow Transplantation, 41, 771–778.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Boitano, A. E., Wang, J., Romeo, R., et al. (2010). Aryl hydrocarbon receptor antagonists promote the expression of human hematopoietic stem cells. Science, 329, 1345–1348.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Peled, T., Shoham, H., Aschengrau, D., et al. (2012). Nicotinamide, a SRT1 inhibitor, inhibits differentiation and facilitates expansion of hematopoietic progenitor cells with enhanced bone marrow homing and engraftment. Experimental Hematology, 40(342–355), e1.

    Google Scholar 

  75. Fares, I., ChagraOUI, J., Gareau, S., et al. (2014). Cord blood expansion. Pyrimidoindole derivatives are agonists of human hematopoietic stem cell renewal. Science, 345, 1509–1512.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Bigas, A., & Espinosa, L. (2012). Hematopoietic stem cells: to be or notch to be. Blood, 119, 3226–3235.

    Article  CAS  PubMed  Google Scholar 

  77. Mayani, H. (2010). Notch signaling: from stem cell expansion to improving cord blood transplantation. Expert Review of Hematology, 3(4), 401–404.

    Article  CAS  PubMed  Google Scholar 

  78. Fajardo-Orduna, G. R., Mayani, H., & Montesinos, J. J. (2015). Hematopoietic support capacity of mesenchymal stem cells: biology and clinical potential. Archives of Medical Research, 46, 589–596.

    Article  CAS  PubMed  Google Scholar 

  79. Wagner, W., Weina, F., Roderburga, C., et al. (2007). Adhesion of hematopoietic progenitor cells to human mesenchymal stem cells as a model for cell-to-cell interaction. Experimental Hematology, 35, 314–325.

    Article  CAS  PubMed  Google Scholar 

  80. Oh, I. H., & Kwon, K. R. (2010). Concise review: multiple niches for hematopoietic stem cell regulation. Stem Cells, 28(7), 1243–1249.

    CAS  PubMed  Google Scholar 

  81. Morrison, S. J., & Scadden, D. T. (2014). The bone marrow niche for hematopoietic stem cells. Nature, 505, 327–334.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Wilson, A., & Trumpp, A. (2006). Bone marrow hematopoietic stem cells niches. Nature Reviews. Immunology, 6, 93–106.

    Article  CAS  PubMed  Google Scholar 

  83. Zhang, J., & Li, L. (2008). Stem cell niche: microenvironment and beyond. Journal of Biological Chemistry, 283(15), 9499–9503.

    Article  CAS  PubMed  Google Scholar 

  84. Ehninger, A., & Trump, A. (2011). The bone marrow stem cell niche grows up: mesenchymal stem cells and macrophages move in. The Journal of Experimental Medicine, 208, 421–428.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Kohler, T., Plettig, R., Wetzstein, W., et al. (1999). Defining optimum conditions for the ex vivo expansion of human umbilical cord blood cells. Influences of progenitor enrichment, interference with feeder layers, early acting cytokines and agitation of culture vessels. Stem Cells, 17, 19–24.

    Article  CAS  PubMed  Google Scholar 

  86. Wagner, W., Roderburg, C., Wein, F., et al. (2007). Molecular and secretary profiles of human mesenchymal stromal cells and their abilities to maintain primitive hematopoietic progenitors. Stem Cells, 25, 2638–2647.

    Article  CAS  PubMed  Google Scholar 

  87. Dexter, T. M., Allen, T. D., & Lajtha, L. G. (1977). Conditions controlling the proliferation of haemopoietic stem cells in vitro. Journal of Cellular Physiology, 91, 335–344.

    Article  CAS  PubMed  Google Scholar 

  88. Kadereit, S., Deeds, L. S., Haynesworth, S. E., et al. (2002). Expansion of LTC-ICs and maintenance of p 21 and BCL-2 expression in cord blood CD34(þ)/CD38(−) early progenitors cultured over human MSCs as a feeder layer. Stem Cells, 20, 573–582.

    Article  CAS  PubMed  Google Scholar 

  89. Yamaguchi, M., Hirayama, F., Murahashi, H., et al. (2002). Ex vivo expansion of human UC blood primitive hematopoietic progenitors and transplantable stem cells using human primary BM stromal cells and human AB serum. Cytotherapy, 4, 109–118.

    Article  CAS  PubMed  Google Scholar 

  90. Alakel, N., Jing, D., Muller, K., Borhauser, M., Ehninger, G., & Ordemann, R. (2009). Direct contact with mesenchymal stromal cells affects migratory behaviour and gene expression profile of CD133+ hematopoietic stem cells during ex vivo expansion. Experimental Hematology, 37, 504–513.

    Article  CAS  PubMed  Google Scholar 

  91. Fong, C. Y., Gauthaman, S., Cheyyatraivendran, S., Lin, H. D., Biswas, A., & Bongso, A. (2012). Human umbilical cord Wharton’s jelly stem cells and its conditioned medium support hematopoietic stem cell expansion ex vivo. Journal of Cellular Biochemistry, 113, 658–668.

    Article  CAS  PubMed  Google Scholar 

  92. de Haan, G., Ploemache, R., The Cobblestone-Area-Forming Cell Assay. Hematopoietic Stem Cell Protocols, Volume 63 of the series Methods in Molecular Medicine pp 143–151.

  93. Majumdar, M. K., Thiede, M. A., & Haynesworth, S. E. (2000). Human marrow-derived mesenchymal stem cells (MSCs) express hematopoietic cytokines and support long-term hematopoiesis when differentiated toward stromal and osteogenic lineages. Hematotherapy Stem Cell Research, 9, 841–848.

    Article  CAS  Google Scholar 

  94. Itkin, T., & Lapidot, T. (2001). SDF-1 keeps HSC quiescent at home. Blood, 117, 373–374.

    Article  Google Scholar 

  95. Bennaceur-Griscelli, A., Pondarre, C., Schiavon, V., Vainchenker, W., & Coulombel, L. (2001). Stromal cells retard the differentiation of CdD4(+)CD38(low/neg) human primitive progenitors exposed to cytokines independent of their mitotic history. Blood, 97, 435–441.

    Article  CAS  PubMed  Google Scholar 

  96. Dao, M. A., Pepper, K. A., & Nolta, J. A. (1997). Long-term cytokine production from engineered primary human stromal cells influences human hematopoiesis in an in vivo xenograft model. Stem Cells, 78, 110–117.

    Google Scholar 

  97. Gottschling, S., Saffrich, R., Seckinger, A., et al. (2007). Human mesenchymal stromal cells regulate initial self-renewing division of hematopoietic progenitor cells by beta-1-integrin dependent mechanism. Stem Cells, 25, 798–806.

    Article  CAS  PubMed  Google Scholar 

  98. Freund, D., Bauer, N., Boxberger, S., et al. (2006). Polarization of hematopoietic progenitors during contact with multipotent mesenchymal stromal cells: effects on proliferation and clonogenecity. Stem Cells and Development, 15(6), 815–829.

    Article  CAS  PubMed  Google Scholar 

  99. Breems, D. A., Blokland, E. A., Siebel, K. E., et al. (1998). Stroma contact prevents loss of hematopoietic stem cell quality during ex vivo expansion of CD34+ mobilized peripheral blood stem cells. Blood, 91(1), 111–117.

    CAS  PubMed  Google Scholar 

  100. Lewis, I. D., Almeida-Porada, G., Du, J., et al. (2001). Umbilical cord blood cells capable of engrafting in primary, secondary, and tertiary, xenogenic hosts are preserved after ex vivo culture in a noncontact system. Blood, 97(11), 3441–3449.

    Article  CAS  PubMed  Google Scholar 

  101. Verfaillie, C. M. (1992). Direct contact between human primitive hematopoietic progenitors and bone marrow stroma is not required for long-term in vitro hematopoiesis. Blood, 79(11), 2821–2826.

    CAS  PubMed  Google Scholar 

  102. da Silva, C. L., Goncalves, R., Cranpnell, K. B., et al. (2005). A human stromal-based serum-free system supports ex vivo expansion/mantainance of bone maroow and cord blood hematopoietic stem/progenitor cells. Experimental Hematology, 33(7), 828–835.

    Article  PubMed  CAS  Google Scholar 

  103. Flores-Guzman, P., Flores-Figueroa, E., Montesinos, J. J., et al. (2009). Individual and combined effects of mesenchymal stromal cells and recombinant stimulatory cytokines on the in vitro growth of primitive hematopoietic cells from human umbilical cord blood. Cytotherapy, 11, 886–896.

    Article  CAS  PubMed  Google Scholar 

  104. Rodriguez-Pardo, V. M., & Vernot, J. P. (2013). Mesenchymal stem cells promote a primitive phenotype CD34 + c-kit + in human cord blood-derived hematopoietic stem cells during ex vivo expansion. Cellular & Molecular Biology Letters, 18, 11–33. doi:10.2478/s11658-012-0036.

    Article  CAS  Google Scholar 

  105. McNiece, I., Harrington, J., Turney, J., Kellner, J., & Shpall, E. J. (2004). Ex vivo expansion of cord blood mononuclear cells on mesenchymal stem cells. Cytotherapy, 6(4), 311–317.

    Article  CAS  PubMed  Google Scholar 

  106. Walenda, T., Bork, S., Horn, et al. (2010). Co-culture with mesenchymal stromal cells increases proliferation and maintenance of haematopoietic progenitor cells. Journal of Cellular and Molecular Medicine, 14, 337–350.

    Article  CAS  PubMed  Google Scholar 

  107. Koh, S. H., Choi, H. S., Park, E. S., Kang, H. J., Ahn, H. S., & Shin, H. Y. (2005). Co-culture of human Cd34+ cells with mesenchymal stem cells increases the survival of Cd34+ cells against the 5-aza-deoxycytidine or trichostatin A-induced cell death. Biochemical and Biophysical Research Communications, 329(3), 1039–1045.

    Article  CAS  PubMed  Google Scholar 

  108. Khoury, M., Drake, A., Chen, Q., et al. (2011). Mesenchymal stem cells secreting angiopoietin-like-5 support efficient expansion of human hematopoietic stem cells without compromising their repopulating potential. Stem Cells and Development, 20, 1371–1381.

    Article  CAS  PubMed  Google Scholar 

  109. Kawano, Y., Kobune, M., Yamaguchi, M., et al. (2003). Ex vivo expansion of human umbilical cord hematopoietic progenitor cells using a coculture system with human telomerase catayitic subunit (hTERT)-transfected human stromal cells. Blood, 101, 532–540.

    Article  CAS  PubMed  Google Scholar 

  110. Leisten, I., Kramann, R., Ventura Ferreira, M. S., Bovi, et al. (2012). 3D co-culture of hematopoietic stem and progenitor cells and mesenchymal stem cells in collagen scaffold as a model of the hematopoietic niche. Biomaterials, 33, 1736–1747.

    Article  CAS  PubMed  Google Scholar 

  111. Ferreira, M. S., Jahnen-Dechenet, W., Labude, N., et al. (2012). Cord blood-hematopoietic stem cell expansion in 3D fibrin scaffolds with stromal support. Biomaterials, 33(29), 6987–6997.

    Article  PubMed  CAS  Google Scholar 

  112. Delalat, B., Pourfathollah, A. A., Soleimani, M., et al. (2009). Isolation and ex vivo expansion of human umbilical cord blood-derived Cd34+ stem cells and their cotransplantation with or without mesenchymal stem cells. Hematology, 14, 125–132.

    Article  PubMed  Google Scholar 

  113. Han, J. Y., Goh, R. H., Seo, S. Y., et al. (2007). Cotransplantation of cord blood hematopoietic stem cells and culture expanded and GM-CSF−/SCF-transfected mesenchymal stem cells in SCID mice. Journal of Korean Medical Science, 22, 242–247.

    Article  PubMed  PubMed Central  Google Scholar 

  114. de Lima, M., McNiece, I., Robinson, S. N., et al. (2012). Cord-blood engraftment with ex vivo mesenchymal-cell culture. New England Journal of Medicine, 367(24), 2305–2315.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Saragusar, R., Lickorish, D., Baksh, D., Hosseini, M. M., & Davies, J. E. (2005). Human umbilical cord perivascular (HUCPV) cells: a source of mesenchymal progenitors. Stem Cells, 23, 220–229.

    Article  Google Scholar 

  116. Bakhshi, T., Zabriskie, R. C., Bodie, S., et al. (2008). Mesenchymal stem cells from the Wharton’s jelly of umbilical cord segments provide stromal support for the maintenance of cord blood hematopoietic stem cells during long-term ex vivo culture. Transfusion, 48, 2638–2644.

    Article  PubMed  PubMed Central  Google Scholar 

  117. Magin, A. S., Korfer, N. R., Pasrtenheimer, H., Lange, C., Zander, A., & Noll, T. (2009). Primary cells as feeder cells for coculture expansion of human hematopoietic stem cells from umbilical cord-blood a comparative study. Stem Cells and Development, 18(1). doi:10.1089/scd.2007.0273.

  118. Tipnis, S., & Viswanathan, C. (2010). Umbilical cord matrix derived mesenchymal stem cells can change the cord blood transplant scenario. International Journal of Stem cells, 3(2), 103–118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Milazzo, L., Vulcano, F., Barca, A., et al. (2014). Cord blood CD34+ cells expanded on Wharton’s jelly multipotent mesenchymal stromal cells improve the hematopoietic engraftment in NOD/SCID mice. European Journal of Haematology, 93(5), 384–391.

    Article  CAS  PubMed  Google Scholar 

  120. Mieog, J. S., de Kruijf, E. M., Bastiaannet, E., et al. (2012). Age determines the prognostic role of the cancer stem cell marker aldehyde dehydrogenase-1 in breast cancer. BMC Cancer, 12(42).

  121. Van der Garde, M., van Pel, M., Millan, R. J. E., et al. (2015). Direct comparison of Wharton’s jelly and bone marrow-derived mesenchymal stromal cells to enhance engraftment of cord blood CD34+ transplants. Stem Cells and Development, 24(22). doi:10.1089/scd.2015.0138.

  122. van der Garde, M., van Hensbergen, Y., Brand, A., Slot, M. C., de Graaf-Dijkstra, A., Mulder, A., Watt, S. M., & Zwaginga, J. J. (2015). Thrombopoietin treatment of one graft in a double cord blood transplant provides early platelet recovery while contributing to long-term engraftment in NSG mice. Stem Cells and Development, 24, 67–76.

    Article  PubMed  CAS  Google Scholar 

  123. van Hensbergen, Y., Schipper, L. F., Brand, A., Slot, M. C., Welling, M., Nauta, A. J., & Fibbe, W. E. (2006). Ex vivo culture of human CD34+ cord blood cells with thrombopoietin (TPO) accelerates platelet engraftment in a NOD/SCID mouse model. Experimental Hematology, 34, 943–950.

    Article  PubMed  CAS  Google Scholar 

  124. Klein, C., Strobel, J., Zingsem, J. et al. (2013). Ex vivo expansion of Hematopoietic Stem-and Progenitor Cells from Cord Blood in co-culture with Mesenchymal stroma cells from Amnion, Chorion, Wharton’s jelly, amniotic Fluid, Cord Blood, and Bone Marrow. Tissue Engineering Part. A, 19 (23and 24), 2577–2585.

  125. Huang, G. P., Pan, Z. J., & Jia, B. B. (2007). Ex vivo expansion and transplantation of hematopoietic stem/progenitor cells supported by mesenchymal stem cells from human umbilical cord blood. Cell Transplantation, 16, 579.

    Article  CAS  PubMed  Google Scholar 

  126. Kedekar, D., Kale, V., & Limaye, L. (2015). Differential ability of MSCs isolated from placenta and cord as feeders for supporting ex vivo expansion of umbilical cord blood derived CD34+ cells. Stem Cell Research & Therapy, 6, 201.

    Article  CAS  Google Scholar 

  127. Mayani, H., Little, M. T., Dragowska, W., Thornbury, G., & Lansdorp, P. M. (1995). Differential effects of the hematopoietic inhibitors MIP-1 alpha, TGF-beta, and TNF-alpha on cytokine-induced proliferation of subpopulations of CD34+ cells purified from cord blood and fetal liver. Experimental Hematology, 5, 422–427.

    Google Scholar 

  128. Wu, K. H., Sheu, J. N., Wu, H. P., et al. (2013). Co-transplantation of umbilical cord- derived mesenchymal stem cells promote hematopoietic engraftment in cord blood transplantation: a pilot study. Clinical and Translation Research, 95(5), 773–777.

    Google Scholar 

  129. Wu, K. H., Tsai, C., Wu, H. P., Sieber, M., Peng, C. T., & Chao, Y. H. (2013). Human application of ex-vivo expanded umbilical cord-derived mesenchymal stem cells: enhance hematopoiesis after cord blood transplantation. Cell Transplantation. doi:10.3727/096368913X663523.

    Google Scholar 

  130. Wu, Y. M., Wang, Z. H., Cao, Y. B., et al. (2013). Co-transplantation of haploidentical hematopoietic and umbilical cord mesenchymal stem cells with a myeloablative regimen for refractory/relapsed hematologic malignancy. Annals of Hematology. doi:10.1007/s00277-013--1831-0.

  131. Chao, Y. H., Tsai, C., Peng, C. T., et al. (2011). Cotransplantation of umbilical cord MSCs to enhance engraftment of hematopoietic stem cells in patients with severe aplastic anemia. Bone Marrow Transplantation, 46(10), 1391–1392.

    Article  PubMed  Google Scholar 

  132. Wu, Y.C., Yongbin, L., Xiaohong et al. (2014). Cotransplantation of haploidentical hematopoietic and umbilical cord mesenchymal stem cells for severe aplastic anemia: successful engraftment and mild GVHD. Stem Cell Research, 12, 132–138.

  133. Holmberg, L. A., Seidel, K., Leisenring, W., & Torok-Storb, B. (1994). Aplastic anemia: analysis of stromal cell function in long-term marrow cultures. Blood, 84, 3685–3690.

    CAS  PubMed  Google Scholar 

  134. Chao, Y. H., Peng, C. T., Harn, H. J., Chan, C. K., & Wu, K. H. (2010). Poor potential of proliferation and differentiation in bone marrow mesenchymal stem cells derived from children with severe aplastic anemia. Annals of Hematology, 89, 715–723.

    Article  PubMed  Google Scholar 

  135. Arai, Y., Aoki, K., Takeda, J., et al. (2015). Clinical significance of high-dose cytarabine added to cyclophosphamide/total-body irradiation in bone marrow or peripheral blood stem cell transplantation for myeloid malignancy. Journal of Hematology & Oncology, 8, 102.

    Article  CAS  Google Scholar 

  136. Chang, Y. J., Zhao, X. Y., Xu, L. P., et al. (2015). Donor-specific anti-human leukocyte antigen antibodies were associated with primary graft failure after unmanipulated haploidentical blood and marrow transplantation: a prospective study with randomly assigned training and validation sets. Journal of Hematology & Oncology, 8, 84.

    Article  CAS  Google Scholar 

  137. Dazzi, F., Ramasamy, R., Glennie, S., Jones, S. P., & Roberts, I. (2006). The role of mesenchymal stem cells in haematopoiesis. Blood Reviews, 20(3), 161–171.

    Article  CAS  PubMed  Google Scholar 

  138. Zhao, K., & Liu, Q. (2016). The clinical application of mesenchymal stromal cells in hematopoietic stem cell transplantation. Journal of Hematology & Oncology, 9, 46.

    Article  Google Scholar 

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Acknowledgements

This work was mainly supported by a grant from PO FESR 4.1.1.1 RIMEDRI (B75f1200150004), funds to SA via the Franco and Piera Cutino Foundation, Palermo. GLR and RA were supported by funding from the IEMEST. The funders had no role in study design, data collections and analysis, decision to publish, or preparation of the article.

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Authors and Affiliations

  1. Campus of Hematology F. and P. Cutino, Villa Sofia-Cervello Hospital, Palermo, Italy

    Melania Lo Iacono, Elena Baiamonte, Aurelio Maggio & Santina Acuto

  2. Euro-Mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy

    Melania Lo Iacono, Rita Anzalone & Giampiero La Rocca

  3. Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy

    Rita Anzalone

  4. Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo, Palermo, Italy

    Giampiero La Rocca

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  1. Melania Lo Iacono
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  2. Rita Anzalone
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Correspondence to Giampiero La Rocca.

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Giampiero La Rocca is member of the Scientific Board of Auxocell laboratories, Inc. The other authors declare no potential conflicts of interest.

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Melania Lo Iacono and Rita Anzalone contributed equally to this paper.

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Lo Iacono, M., Anzalone, R., La Rocca, G. et al. Wharton’s Jelly Mesenchymal Stromal Cells as a Feeder Layer for the Ex Vivo Expansion of Hematopoietic Stem and Progenitor Cells: a Review. Stem Cell Rev and Rep 13, 35–49 (2017). https://doi.org/10.1007/s12015-016-9702-4

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