J Korean Orthop Assoc.  2019 Dec;54(6):490-497. 10.4055/jkoa.2019.54.6.490.

Clinical Use of Mesenchymal Stem Cells in Bone Regeneration

• Park CW
• Lim SJ
• Park YS

• KMID: 2469880
• DOI: http://doi.org/10.4055/jkoa.2019.54.6.490

Abstract

Owing to the recent advances in biological knowledge on stem cells, many efforts are being made to apply them to clinical practice. Although mesenchymal stem cells were first found in bone marrow aspirates, they are understood to be multipotent stromal cells that can be extracted from a variety of tissues, such as adipose, dermal, skeletal muscle, and umbilical-cord tissues. The osteogenicity of mesenchymal stem cells has been verified through various experiments and animal studies. Some successful bone regenerations have also been reported in difficult clinical situations, such as large bone defects, osteonecrosis, and nonunion. On the other hand, there are no standardized indications or application methods for each clinical situation, and convincing evidence of its efficacy and safety is still lacking. Bone regeneration therapies using mesenchymal stem cells are likely to expand further in the future, but there are some issues that need to be addressed in order for them be recognized as standard treatments.

Keyword

mesenchymal stem cell; bone regeneration; bone marrow; osteonecrosis; nonunion

MeSH Terms

Animals
Bone Marrow
Bone Regeneration*
Hand
Mesenchymal Stromal Cells*
Muscle, Skeletal
Osteonecrosis
Stem Cells
Stromal Cells

Reference

1. Walmsley GG, Ransom RC, Zielins ER, et al. Stem cells in bone regeneration. Stem Cell Rev. 2016; 12:524–529.

2. Fisher JN, Peretti GM, Scotti C. Stem cells for bone regeneration: from cell-based therapies to decellularised engineered extracellular matrices. Stem Cells Int. 2016; 2016:9352598.

3. Grayson WL, Bunnell BA, Martin E, Frazier T, Hung BP, Gimble JM. Stromal cells and stem cells in clinical bone regeneration. Nat Rev Endocrinol. 2015; 11:140–150.

4. Caplan AI. Mesenchymal stem cells. J Orthop Res. 1991; 9:641–650.

5. Wakitani S, Saito T, Caplan AI. Myogenic cells derived from rat bone marrow mesenchymal stem cells exposed to 5-azacytidine. Muscle Nerve. 1995; 18:1417–1426.

6. Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999; 284:143–147.

7. Yousefi AM, James PF, Akbarzadeh R, Subramanian A, Flavin C, Oudadesse H. Prospect of stem cells in bone tissue engineering: a review. Stem Cells Int. 2016; 2016:6180487.

8. James AW, Zara JN, Corselli M, et al. An abundant perivascular source of stem cells for bone tissue engineering. Stem Cells Transl Med. 2012; 1:673–684.

9. Bose S, Roy M, Bandyopadhyay A. Recent advances in bone tissue engineering scaffolds. Trends Biotechnol. 2012; 30:546–554.

10. Boroviak T, Loos R, Bertone P, Smith A, Nichols J. The ability of inner-cell-mass cells to self-renew as embryonic stem cells is acquired following epiblast specification. Nat Cell Biol. 2014; 16:516–528.

11. Kumar R, Sharma A, Pattnaik AK, Varadwaj PK. Stem cells: an overview with respect to cardiovascular and renal disease. J Nat Sci Biol Med. 2010; 1:43–52.

12. Friedenstein AJ. Precursor cells of mechanocytes. Int Rev Cytol. 1976; 47:327–359.

13. Friedenstein AJ, Lalykina KS. Thymus cells are inducible to osteogenesis. Eur J Immunol. 1972; 2:602–603.

14. Friedenstein AJ, Petrakova KV, Kurolesova AI, Frolova GP. Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation. 1968; 6:230–247.

15. Friedenstein AJ, Deriglasova UF, Kulagina NN, et al. Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method. Exp Hematol. 1974; 2:83–92.

16. Lanotte M, Scott D, Dexter TM, Allen TD. Clonal preadipocyte cell lines with different phenotypes derived from murine marrow stroma: factors influencing growth and adipogenesis in vitro. J Cell Physiol. 1982; 111:177–186.

17. Hunt P, Robertson D, Weiss D, Rennick D, Lee F, Witte ON. A single bone marrow-derived stromal cell type supports the in vitro growth of early lymphoid and myeloid cells. Cell. 1987; 48:997–1007.

18. Pietrangeli CE, Hayashi S, Kincade PW. Stromal cell lines which support lymphocyte growth: characterization, sensitivity to radiation and responsiveness to growth factors. Eur J Immunol. 1988; 18:863–872.

19. Whitlock CA, Tidmarsh GF, Muller-Sieburg C, Weissman IL. Bone marrow stromal cell lines with lymphopoietic activity express high levels of a pre-B neoplasia-associated molecule. Cell. 1987; 48:1009–1021.

20. Caplan AI. Mesenchymal stem cells: time to change the name! Stem Cells Transl Med. 2017; 6:1445–1451.

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

22. Maiti SK, Ninu AR, Sangeetha P, et al. Mesenchymal stem cells-seeded bio-ceramic construct for bone regeneration in large critical-size bone defect in rabbit. J Stem Cells Regen Med. 2016; 12:87–99.

23. Killington K, Mafi R, Mafi P, Khan WS. A systematic review of clinical studies investigating mesenchymal stem cells for fracture non-union and bone defects. Curr Stem Cell Res Ther. 2018; 13:284–291.

24. Plock JA, Schnider JT, Zhang W, et al. Adipose- and bone marrow-derived mesenchymal stem cells prolong graft survival in vascularized composite allotransplantation. Transplantation. 2015; 99:1765–1773.

25. Wang M, Yuan Q, Xie L. Mesenchymal stem cell-based immunomodulation: properties and clinical application. Stem Cells Int. 2018; 2018:3057624.

26. Gebler A, Zabel O, Seliger B. The immunomodulatory capacity of mesenchymal stem cells. Trends Mol Med. 2012; 18:128–134.

27. Jin YZ, Lee JH. Mesenchymal stem cell therapy for bone regeneration. Clin Orthop Surg. 2018; 10:271–278.

28. Bourin P, Bunnell BA, Casteilla L, et al. Stromal cells from the adipose tissue-derived stromal vascular fraction and culture expanded adipose tissue-derived stromal/stem cells: a joint statement of the International Federation for Adipose Therapeutics and Science (IFATS) and the International Society for Cellular Therapy (ISCT). Cytotherapy. 2013; 15:641–648.

29. Jin HJ, Bae YK, Kim M, et al. Comparative analysis of human mesenchymal stem cells from bone marrow, adipose tissue, and umbilical cord blood as sources of cell therapy. Int J Mol Sci. 2013; 14:17986–18001.

30. Kern S, Eichler H, Stoeve J, Klüter H, Bieback K. Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells. 2006; 24:1294–1301.

31. Asatrian G, Pham D, Hardy WR, James AW, Peault B. Stem cell technology for bone regeneration: current status and potential applications. Stem Cells Cloning. 2015; 8:39–48.

32. Yu G, Floyd ZE, Wu X, Halvorsen YD, Gimble JM. Isolation of human adipose-derived stem cells from lipoaspirates. Methods Mol Biol. 2011; 702:17–27.

33. Aust L, Devlin B, Foster SJ, et al. Yield of human adipose-derived adult stem cells from liposuction aspirates. Cytotherapy. 2004; 6:7–14.

34. Im GI, Shin YW, Lee KB. Do adipose tissue-derived mesenchymal stem cells have the same osteogenic and chondrogenic potential as bone marrow-derived cells? Osteoarthritis Cartilage. 2005; 13:845–853.

35. Hayashi O, Katsube Y, Hirose M, Ohgushi H, Ito H. Comparison of osteogenic ability of rat mesenchymal stem cells from bone marrow, periosteum, and adipose tissue. Calcif Tissue Int. 2008; 82:238–247.

36. Crisan M, Corselli M, Chen WC, Péault B. Perivascular cells for regenerative medicine. J Cell Mol Med. 2012; 16:2851–2860.

37. James AW, Zara JN, Zhang X, et al. Perivascular stem cells: a prospectively purified mesenchymal stem cell population for bone tissue engineering. Stem Cells Transl Med. 2012; 1:510–519.

38. Corselli M, Crisan M, Murray IR, et al. Identification of perivascular mesenchymal stromal/stem cells by flow cytometry. Cytometry A. 2013; 83:714–720.

39. Weiss ML, Troyer DL. Stem cells in the umbilical cord. Stem Cell Rev. 2006; 2:155–162.

40. Cairo MS, Wagner JE. Placental and/or umbilical cord blood: an alternative source of hematopoietic stem cells for transplantation. Blood. 1997; 90:4665–4678.

41. Rocha V, Gluckman E. Eurocord and European Blood and Marrow Transplant Group. Clinical use of umbilical cord blood hematopoietic stem cells. Biol Blood Marrow Transplant. 2006; 12:1 Suppl 1. 34–41.

42. Yang SE, Ha CW, Jung M, et al. Mesenchymal stem/progenitor cells developed in cultures from UC blood. Cytotherapy. 2004; 6:476–486.

43. Park YB, Ha CW, Lee CH, Yoon YC, Park YG. Cartilage regeneration in osteoarthritic patients by a composite of allogeneic umbilical cord blood-derived mesenchymal stem cells and hyaluronate hydrogel: results from a clinical trial for safety and proof-of-concept with 7 years of extended follow-up. Stem Cells Transl Med. 2017; 6:613–621.

44. Li H, Johnson NR, Usas A, et al. Sustained release of bone morphogenetic protein 2 via coacervate improves the osteogenic potential of muscle-derived stem cells. Stem Cells Transl Med. 2013; 2:667–677.

45. Usas A, Mačiulaitis J, Mačiulaitis R, Jakubonienė N, Milašius A, Huard J. Skeletal muscle-derived stem cells: implications for cell-mediated therapies. Medicina (Kaunas). 2011; 47:469–479.

46. Connolly JF, Guse R, Tiedeman J, Dehne R. Autologous marrow injection as a substitute for operative grafting of tibial nonunions. Clin Orthop Relat Res. 1991; (266):259–270.

47. Garg NK, Gaur S, Sharma S. Percutaneous autogenous bone marrow grafting in 20 cases of ununited fracture. Acta Orthop Scand. 1993; 64:671–672.

48. Goel A, Sangwan SS, Siwach RC, Ali AM. Percutaneous bone marrow grafting for the treatment of tibial non-union. Injury. 2005; 36:203–206.

49. Liebergall M, Schroeder J, Mosheiff R, et al. Stem cell-based therapy for prevention of delayed fracture union: a randomized and prospective preliminary study. Mol Ther. 2013; 21:1631–1638.

50. Ismail HD, Phedy P, Kholinne E, et al. Mesenchymal stem cell implantation in atrophic nonunion of the long bones: a translational study. Bone Joint Res. 2016; 5:287–293.

51. Steinberg ME, Larcom PG, Strafford B, et al. Core decompression with bone grafting for osteonecrosis of the femoral head. Clin Orthop Relat Res. 2001; (386):71–78.

52. Pierce TP, Jauregui JJ, Elmallah RK, Lavernia CJ, Mont MA, Nace J. A current review of core decompression in the treatment of osteonecrosis of the femoral head. Curr Rev Musculoskelet Med. 2015; 8:228–232.

53. Hernigou P, Beaujean F. Treatment of osteonecrosis with autologous bone marrow grafting. Clin Orthop Relat Res. 2002; (405):14–23.

54. Gangji V, Hauzeur JP, Matos C, De Maertelaer V, Toungouz M, Lambermont M. Treatment of osteonecrosis of the femoral head with implantation of autologous bone-marrow cells A pilot study. J Bone Joint Surg Am. 2004; 86:1153–1160.

55. Mao Q, Jin H, Liao F, Xiao L, Chen D, Tong P. The efficacy of targeted intraarterial delivery of concentrated autologous bone marrow containing mononuclear cells in the treatment of osteonecrosis of the femoral head: a five year follow-up study. Bone. 2013; 57:509–516.

56. Zhao D, Cui D, Wang B, et al. Treatment of early stage osteonecrosis of the femoral head with autologous implantation of bone marrow-derived and cultured mesenchymal stem cells. Bone. 2012; 50:325–330.

57. Im GI. Stem cell therapy in osteonecrosis of the femoral head. Hip Pelvis. 2018; 30:135–137.

58. Hernigou P, Flouzat-Lachaniette CH, Delambre J, et al. Osteonecrosis repair with bone marrow cell therapies: state of the clinical art. Bone. 2015; 70:102–109.

59. Warnke PH, Springer IN, Wiltfang J, et al. Growth and transplantation of a custom vascularised bone graft in a man. Lancet. 2004; 364:766–770.

60. Mesimäki K, Lindroos B, Törnwall J, et al. Novel maxillary reconstruction with ectopic bone formation by GMP adipose stem cells. Int J Oral Maxillofac Surg. 2009; 38:201–209.

61. Sándor GK, Numminen J, Wolff J, et al. Adipose stem cells used to reconstruct 13 cases with cranio-maxillofacial hard-tissue defects. Stem Cells Transl Med. 2014; 3:530–540.

62. Lendeckel S, Jödicke A, Christophis P, et al. Autologous stem cells (adipose) and fibrin glue used to treat widespread traumatic calvarial defects: case report. J Craniomaxillofac Surg. 2004; 32:370–373.

63. Ajiboye RM, Eckardt MA, Hamamoto JT, Plotkin B, Daubs MD, Wang JC. Outcomes of Demineralized bone matrix enriched with concentrated bone marrow aspirate in lumbar fusion. Int J Spine Surg. 2016; 10:35.

64. Ammerman JM, Libricz J, Ammerman MD. The role of Osteocel Plus as a fusion substrate in minimally invasive instrumented transforaminal lumbar interbody fusion. Clin Neurol Neurosurg. 2013; 115:991–994.

65. Dupont KM, Sharma K, Stevens HY, Boerckel JD, García AJ, Guldberg RE. Human stem cell delivery for treatment of large segmental bone defects. Proc Natl Acad Sci U S A. 2010; 107:3305–3310.

66. Musacchio E, Veronese N. Bone regeneration in the stem cell era: safe play for the patient? Clin Rheumatol. 2017; 36:745–752.

67. Foroutan T, Najmi M, Kazemi N, Hasanlou M, Pedram A. Lower oncogenic potential of human mesenchymal stem cells derived from cord blood compared to induced pluripotent stem cells. Int J Organ Transplant Med. 2015; 6:99–104.