Research progress of intervertebral disc endogenous stem cells for intervertebral disc regeneration_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

LIANG Hang , DENG Xiangyu ,  SHAO Zengwu

Orthopaedic Hospital, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan Hubei, 430022, P.R.China;

Corresponding author：

SHAO Zengwu, Email: szwpro@163.com

Keywords：

Intervertebral disc degeneration; endogenous stem cells; repair and regeneration

DOI：

10.7507/1002-1892.201703036

Video：

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Objective To summarize the research progress of intervertebral disc endogenous stem cells for intervertebral disc regeneration and deduce the therapeutic potential of endogenous repair for intervertebral disc degeneration. Methods The original articles about intervertebral disc endogenous stem cells for intervertebral disc regeneration were extensively reviewed; the reparative potential in vivo and the extraction and identification in vitro of intervertebral disc endogenous stem cells were analyzed; the prospect of endogenous stem cells for intervertebral disc regeneration was predicted. Results Stem cell niche present in the intervertebral discs, from which stem cells migrate to injured tissues and contribute to tissues regeneration under certain specific microenvironment. Moreover, the migration of stem cells is regulated by chemokines system. Tissue specific progenitor cells have been identified and successfully extracted and isolated. The findings provide the basis for biological therapy of intervertebral disc endogenous stem cells. Conclusion Intervertebral disc endogenous stem cells play a crucial role in intervertebral disc regeneration. Therapeutic strategy of intervertebral disc endogenous stem cells is proven to be a promising biological approach for intervertebral disc regeneration.

Citation： LIANG Hang, DENG Xiangyu, SHAO Zengwu. Research progress of intervertebral disc endogenous stem cells for intervertebral disc regeneration. Chinese Journal of Reparative and Reconstructive Surgery, 2017, 31(10): 1267-1272. doi: 10.7507/1002-1892.201703036 Copy

1.	Lively MW. Sports medicine approach to low back pain. South Med J, 2002, 95(6): 642-646.
2.	Cheung KM, Karppinen J, Chan D, et al. Prevalence and pattern of lumbar magnetic resonance imaging changes in a population study of one thousand forty-three individuals. Spine (Phila Pa 1976), 2009, 34(9): 934-940.
3.	Samartzis D, Karppinen J, Mok F, et al. A population-based study of juvenile disc degeneration and its association with overweight and obesity, low back pain, and diminished functional status. J Bone Joint Surg (Am), 2011, 93(7): 662-670.
4.	Takatalo J, Karppinen J, Niinimäki J, et al. Does lumbar disc degeneration on magnetic resonance imaging associate with low back symptom severity in young Finnish adults? Spine (Phila Pa 1976), 2011, 36(25): 2180-2189.
5.	Dagenais S, Caro J, Haldeman S. A systematic review of low back pain cost of illness studies in the United States and internationally. Spine J, 2008, 8(1): 8-20.
6.	Alman B, Kelley S, Nam D. Heal thyself: using endogenous regeneration to repair bone. Tissue Eng Part B Rev, 2011, 17(6): 431-436.
7.	Forbes SJ, Rosenthal N. Preparing the ground for tissue regeneration: from mechanism to therapy. Nat Med, 2014, 20(8): 857-869.
8.	Brodin H. Paths of nutrition in articular cartilage and intervertebral discs. Acta Orthop Scand, 1955, 24(3): 177-183.
9.	Grunhagen T, Shirazi-Adl A, Fairbank JC, et al. Intervertebral disk nutrition: a review of factors influencing concentrations of nutrients and metabolites. Orthop Clin North Am, 2011, 42(4): 465-477.
10.	Holm S, Maroudas A, Urban JP, et al. Nutrition of the intervertebral disc: solute transport and metabolism. Connect Tissue Res, 1981, 8(2): 101-119.
11.	Risbud MV, Shapiro IM. Role of cytokines in intervertebral disc degeneration: pain and disc content. Nat Rev Rheumatol, 2014, 10(1): 44-56.
12.	Candela ME, Yasuhara R, Iwamoto M, et al. Resident mesenchymal progenitors of articular cartilage. Matrix Biol, 2014, 39: 44-49.
13.	Seta N, Kuwana M. Human circulating monocytes as multipotential progenitors. Keio J Med, 2007, 56(2): 41-47.
14.	Henriksson H, Thornemo M, Karisson C, et al. Identification of cell proliferation zones, progenitor cells and a potential stem cell niche in the intervertebral disc region: a study in four species. Spine (Phila Pa 1976), 2009, 34(21): 2278-2287.
15.	Voog J, Jones DL. Stem cells and the niche: a dynamic duo. Cell Stem Cell, 2010, 6(2): 103-115.
16.	Henriksson HB, Svala E, Skioldebrand E, et al. Support of concept that migrating progenitor cells from stem cell niches contribute to normal regeneration of the adult mammal intervertebral disc: a descriptive study in the New Zealand white rabbit. Spine (Phila Pa 1976), 2012, 37(9): 722-732.
17.	Hiyama A, Mochida J, Iwashina T, et al. Transplantation of mesenchymal stem cells in a canine disc degeneration model. J Orthop Res, 2008, 26(5): 589-600.
18.	Serigano K, Sakai D, Hiyama A, et al. Effect of cell number on mesenchymal stem cell transplantation in a canine disc degeneration model. J Orthop Res, 2010, 28(10): 1267-1275.
19.	Feng G, Zhao X, Liu H, et al. Transplantation of mesenchymal stem cells and nucleus pulposus cells in a degenerative disc model in rabbits: a comparison of 2 cell types as potential candidates for disc regeneration. J Neurosurg Spine, 2011, 14(3): 322-329.
20.	Anderson DG, Markova D, An HS, et al. Human umbilical cord blood-derived mesenchymal stem cells in the cultured rabbit intervertebral disc: a novel cell source for disc repair. Am J Phys Med Rehabil, 2013, 92(5): 420-429.
21.	Wang H, Zhou Y, Huang B, et al. Utilization of stem cells in alginate for nucleus pulposus tissue engineering. Tissue Eng Part A, 2014, 20(5-6): 908-920.
22.	Watanabe T, Sakai Dm Yamamoto Y, et al. Human nucleus pulposus cells significantly enhanced biological properties in a coculture system with direct cell-to-cell contact with autologous mesenchymal stem cells. J Orthop Res, 2010, 28(5): 623-630.
23.	Miyamoto T, Muneta T, Tabuchi T, et al. Intradiscal transplantation of synovial mesenchymal stem cells prevents intervertebral disc degeneration through suppression of matrix metalloproteinase-related genes in nucleus pulposus cells in rabbits. Arthritis Res Ther, 2010, 12(6): R206.
24.	Omlor GW, Bertram H, Kleinschmidt K, et al. Methods to monitor distribution and metabolic activity of mesenchymal stem cells following in vivo injection into nucleotomized porcine intervertebral discs. Eur Spine J, 2010, 19(4): 601-612.
25.	Vadalà G, Sowa G, Hubert M, et al. Mesenchymal stem cells injection in degenerated intervertebral disc: cell leakage may induce osteophyte formation. J Tissue Eng Regen Med, 2012, 6(5): 348-355.
26.	Halaschek-Wiener J, Brooks-Wilson A. Progeria of stem cells: stem cell exhaustion in Hutchinson-Gilford progeria syndrome. J Gerontol A Biol Sci Med Sci, 2007, 62(1): 3-8.
27.	Vanden Berg-Foels WS. In situ tissue regeneration: chemoattractants for endogenous stem cell recruitment. Tissue Eng Part B Rev, 2014, 20(1): 28-39.
28.	Illien-Jünger S, Pattappa G, Peroglio M, et al. Homing of mesenchymal stem cells in induced degenerative intervertebral discs in a whole organ culture system. Spine (Phila Pa 1976), 2012, 37(22): 1865-1873.
29.	Baek SJ, Kang SK, Ra JC. In vitro migration capacity of human adipose tissue-derived mesenchymal stem cells reflects their expression of receptors for chemokines and growth factors. Exp Mol Med, 2011, 43(10): 596-603.
30.	Lee MJ, Kim J, Kim MY, et al. Proteomic analysis of tumor necrosis factor-alpha-induced secretome of human adipose tissue-derived mesenchymal stem cells. J Proteome Res, 2010, 9(4): 1754-1762.
31.	Pereira CL, Gonçalves RM, Peroglio M, et al. The effect of hyaluronan-based delivery of stromal cell-derived factor-1 on the recruitment of MSCs in degenerating intervertebral discs. Biomaterials, 2014, 35(28): 8144-8153.
32.	Pattappa G, Peroglio M, Sakai D, et al. CCL5/RANTES is a key chemoattractant released by degenerative intervertebral discs in organ culture. Eur Cell Mater, 2014, 27: 124-136.
33.	Gruber HE, Hoelscher GL, Ingram JA, et al. Production and expression of RANTES (CCL5) by human disc cells and modulation by IL-1-beta and TNF-alpha in 3D culture. Exp Mol Pathol, 2014, 96(2): 133-138.
34.	Kepler CK, Markova DZ, Dibra F, et al. Expression and relationship of proinflammatory chemokine RANTES/CCL5 and cytokine IL-1beta in painful human intervertebral discs. Spine (Phila Pa 1976), 2013, 38(11): 873-880.
35.	Li H, Zou X, Baatrup A, et al. Cytokine profiles in conditioned media from cultured human intervertebral disc tissue. Implications of their effect on bone marrow stem cell metabolism. Acta Orthop, 2005, 76(1): 115-121.
36.	Phillips KL, Chiverton N, Michael AL, et al. The cytokine and chemokine expression profile of nucleus pulposus cells: implications for degeneration and regeneration of the intervertebral disc. Arthritis Res Ther, 2013, 15(6): R213.
37.	Xiong CJ, Huang B, Zhou Y, et al. Macrophage migration inhibitory factor inhibits the migration of cartilage end plate-derived stem cells by reacting with CD74. PLoS One, 2012, 7(8): e43984.
38.	Blanco JF, Graciani IF, Sanchez-Guijo FM, et al. Isolation and characterization of mesenchymal stromal cells from human degenerated nucleus pulposus: comparison with bone marrow mesenchymal stromal cells from the same subjects. Spine (Phila Pa 1976), 2010, 35(26): 2259-2265.
39.	Erwin WM, Islam D, Eftekarpour E, et al. Intervertebral disc-derived stem cells: implications for regenerative medicine and neural repair. Spine (Phila Pa 1976), 2013, 38(3): 211-216.
40.	Feng G, Yang X, Shang H, et al. Multipotential differentiation of human anulus fibrosus cells: an in vitro study. J Bone Joint Surg (Am), 2010, 92(3): 675-685.
41.	Liu LT, Huang B, Li CQ, et al. Characteristics of stem cells derived from the degenerated human intervertebral disc cartilage endplate. PLoS One, 2011, 6(10): e26285.
42.	Wang H, Zhou Y, Chu TW, et al. Distinguishing characteristics of stem cells derived from different anatomical regions of human degenerated intervertebral discs. Eur Spine J, 2016, 25(9): 2691-2704.
43.	Liu S, Liang H, Lee SM, et al. Isolation and identification of stem cells from degenerated human intervertebral discs and their migration characteristics. Acta Biochim Biophys Sin (Shanghai), 2017, 49(2): 101-109.
44.	Risbud MV, Guttapalli A, Tsai TT, et al. Evidence for skeletal progenitor cells in the degenerate human intervertebral disc. Spine (Phila Pa 1976), 2007, 32(23): 2537-2544.
45.	Sakai D, Nakamura Y, Nakai T, et al. Exhaustion of nucleus pulposus progenitor cells with ageing and degeneration of the intervertebral disc. Nat Commun, 2012, 3: 1264.
46.	Yasen M, Fei Q, Hutton WC, et al. Changes of number of cells expressing proliferation and progenitor cell markers with age in rabbit intervertebral discs. Acta Biochim Biophys Sin (Shanghai), 2013, 45(5): 368-376.
47.	Brisby H, Papadimitriou N, Brantsing C, et al. The presence of local mesenchymal progenitor cells in human degenerated intervertebral discs and possibilities to influence these in vitro: a descriptive study in humans. Stem Cells Dev, 2013, 22(5): 804-814.
48.	Guan X, Ma X, Zhang L, et al. Evaluation of CD24 as a marker to rapidly define the mesenchymal stem cell phenotype and its differentiation in human nucleus pulposus. Chin Med J (Engl), 2014, 127(8): 1474-1481.
49.	Peroglio M, Grad S, Mortisen D, et al. Injectable thermoreversible hyaluronan-based hydrogels for nucleus pulposus cell encapsulation. Eur Spine J, 2012, 21 Suppl 6: S839-849.

1. Lively MW. Sports medicine approach to low back pain. South Med J, 2002, 95(6): 642-646.
2. Cheung KM, Karppinen J, Chan D, et al. Prevalence and pattern of lumbar magnetic resonance imaging changes in a population study of one thousand forty-three individuals. Spine (Phila Pa 1976), 2009, 34(9): 934-940.
3. Samartzis D, Karppinen J, Mok F, et al. A population-based study of juvenile disc degeneration and its association with overweight and obesity, low back pain, and diminished functional status. J Bone Joint Surg (Am), 2011, 93(7): 662-670.
4. Takatalo J, Karppinen J, Niinimäki J, et al. Does lumbar disc degeneration on magnetic resonance imaging associate with low back symptom severity in young Finnish adults? Spine (Phila Pa 1976), 2011, 36(25): 2180-2189.
5. Dagenais S, Caro J, Haldeman S. A systematic review of low back pain cost of illness studies in the United States and internationally. Spine J, 2008, 8(1): 8-20.
6. Alman B, Kelley S, Nam D. Heal thyself: using endogenous regeneration to repair bone. Tissue Eng Part B Rev, 2011, 17(6): 431-436.
7. Forbes SJ, Rosenthal N. Preparing the ground for tissue regeneration: from mechanism to therapy. Nat Med, 2014, 20(8): 857-869.
8. Brodin H. Paths of nutrition in articular cartilage and intervertebral discs. Acta Orthop Scand, 1955, 24(3): 177-183.
9. Grunhagen T, Shirazi-Adl A, Fairbank JC, et al. Intervertebral disk nutrition: a review of factors influencing concentrations of nutrients and metabolites. Orthop Clin North Am, 2011, 42(4): 465-477.
10. Holm S, Maroudas A, Urban JP, et al. Nutrition of the intervertebral disc: solute transport and metabolism. Connect Tissue Res, 1981, 8(2): 101-119.
11. Risbud MV, Shapiro IM. Role of cytokines in intervertebral disc degeneration: pain and disc content. Nat Rev Rheumatol, 2014, 10(1): 44-56.
12. Candela ME, Yasuhara R, Iwamoto M, et al. Resident mesenchymal progenitors of articular cartilage. Matrix Biol, 2014, 39: 44-49.
13. Seta N, Kuwana M. Human circulating monocytes as multipotential progenitors. Keio J Med, 2007, 56(2): 41-47.
14. Henriksson H, Thornemo M, Karisson C, et al. Identification of cell proliferation zones, progenitor cells and a potential stem cell niche in the intervertebral disc region: a study in four species. Spine (Phila Pa 1976), 2009, 34(21): 2278-2287.
15. Voog J, Jones DL. Stem cells and the niche: a dynamic duo. Cell Stem Cell, 2010, 6(2): 103-115.
16. Henriksson HB, Svala E, Skioldebrand E, et al. Support of concept that migrating progenitor cells from stem cell niches contribute to normal regeneration of the adult mammal intervertebral disc: a descriptive study in the New Zealand white rabbit. Spine (Phila Pa 1976), 2012, 37(9): 722-732.
17. Hiyama A, Mochida J, Iwashina T, et al. Transplantation of mesenchymal stem cells in a canine disc degeneration model. J Orthop Res, 2008, 26(5): 589-600.
18. Serigano K, Sakai D, Hiyama A, et al. Effect of cell number on mesenchymal stem cell transplantation in a canine disc degeneration model. J Orthop Res, 2010, 28(10): 1267-1275.
19. Feng G, Zhao X, Liu H, et al. Transplantation of mesenchymal stem cells and nucleus pulposus cells in a degenerative disc model in rabbits: a comparison of 2 cell types as potential candidates for disc regeneration. J Neurosurg Spine, 2011, 14(3): 322-329.
20. Anderson DG, Markova D, An HS, et al. Human umbilical cord blood-derived mesenchymal stem cells in the cultured rabbit intervertebral disc: a novel cell source for disc repair. Am J Phys Med Rehabil, 2013, 92(5): 420-429.
21. Wang H, Zhou Y, Huang B, et al. Utilization of stem cells in alginate for nucleus pulposus tissue engineering. Tissue Eng Part A, 2014, 20(5-6): 908-920.
22. Watanabe T, Sakai Dm Yamamoto Y, et al. Human nucleus pulposus cells significantly enhanced biological properties in a coculture system with direct cell-to-cell contact with autologous mesenchymal stem cells. J Orthop Res, 2010, 28(5): 623-630.
23. Miyamoto T, Muneta T, Tabuchi T, et al. Intradiscal transplantation of synovial mesenchymal stem cells prevents intervertebral disc degeneration through suppression of matrix metalloproteinase-related genes in nucleus pulposus cells in rabbits. Arthritis Res Ther, 2010, 12(6): R206.
24. Omlor GW, Bertram H, Kleinschmidt K, et al. Methods to monitor distribution and metabolic activity of mesenchymal stem cells following in vivo injection into nucleotomized porcine intervertebral discs. Eur Spine J, 2010, 19(4): 601-612.
25. Vadalà G, Sowa G, Hubert M, et al. Mesenchymal stem cells injection in degenerated intervertebral disc: cell leakage may induce osteophyte formation. J Tissue Eng Regen Med, 2012, 6(5): 348-355.
26. Halaschek-Wiener J, Brooks-Wilson A. Progeria of stem cells: stem cell exhaustion in Hutchinson-Gilford progeria syndrome. J Gerontol A Biol Sci Med Sci, 2007, 62(1): 3-8.
27. Vanden Berg-Foels WS. In situ tissue regeneration: chemoattractants for endogenous stem cell recruitment. Tissue Eng Part B Rev, 2014, 20(1): 28-39.
28. Illien-Jünger S, Pattappa G, Peroglio M, et al. Homing of mesenchymal stem cells in induced degenerative intervertebral discs in a whole organ culture system. Spine (Phila Pa 1976), 2012, 37(22): 1865-1873.
29. Baek SJ, Kang SK, Ra JC. In vitro migration capacity of human adipose tissue-derived mesenchymal stem cells reflects their expression of receptors for chemokines and growth factors. Exp Mol Med, 2011, 43(10): 596-603.
30. Lee MJ, Kim J, Kim MY, et al. Proteomic analysis of tumor necrosis factor-alpha-induced secretome of human adipose tissue-derived mesenchymal stem cells. J Proteome Res, 2010, 9(4): 1754-1762.
31. Pereira CL, Gonçalves RM, Peroglio M, et al. The effect of hyaluronan-based delivery of stromal cell-derived factor-1 on the recruitment of MSCs in degenerating intervertebral discs. Biomaterials, 2014, 35(28): 8144-8153.
32. Pattappa G, Peroglio M, Sakai D, et al. CCL5/RANTES is a key chemoattractant released by degenerative intervertebral discs in organ culture. Eur Cell Mater, 2014, 27: 124-136.
33. Gruber HE, Hoelscher GL, Ingram JA, et al. Production and expression of RANTES (CCL5) by human disc cells and modulation by IL-1-beta and TNF-alpha in 3D culture. Exp Mol Pathol, 2014, 96(2): 133-138.
34. Kepler CK, Markova DZ, Dibra F, et al. Expression and relationship of proinflammatory chemokine RANTES/CCL5 and cytokine IL-1beta in painful human intervertebral discs. Spine (Phila Pa 1976), 2013, 38(11): 873-880.
35. Li H, Zou X, Baatrup A, et al. Cytokine profiles in conditioned media from cultured human intervertebral disc tissue. Implications of their effect on bone marrow stem cell metabolism. Acta Orthop, 2005, 76(1): 115-121.
36. Phillips KL, Chiverton N, Michael AL, et al. The cytokine and chemokine expression profile of nucleus pulposus cells: implications for degeneration and regeneration of the intervertebral disc. Arthritis Res Ther, 2013, 15(6): R213.
37. Xiong CJ, Huang B, Zhou Y, et al. Macrophage migration inhibitory factor inhibits the migration of cartilage end plate-derived stem cells by reacting with CD74. PLoS One, 2012, 7(8): e43984.
38. Blanco JF, Graciani IF, Sanchez-Guijo FM, et al. Isolation and characterization of mesenchymal stromal cells from human degenerated nucleus pulposus: comparison with bone marrow mesenchymal stromal cells from the same subjects. Spine (Phila Pa 1976), 2010, 35(26): 2259-2265.
39. Erwin WM, Islam D, Eftekarpour E, et al. Intervertebral disc-derived stem cells: implications for regenerative medicine and neural repair. Spine (Phila Pa 1976), 2013, 38(3): 211-216.
40. Feng G, Yang X, Shang H, et al. Multipotential differentiation of human anulus fibrosus cells: an in vitro study. J Bone Joint Surg (Am), 2010, 92(3): 675-685.
41. Liu LT, Huang B, Li CQ, et al. Characteristics of stem cells derived from the degenerated human intervertebral disc cartilage endplate. PLoS One, 2011, 6(10): e26285.
42. Wang H, Zhou Y, Chu TW, et al. Distinguishing characteristics of stem cells derived from different anatomical regions of human degenerated intervertebral discs. Eur Spine J, 2016, 25(9): 2691-2704.
43. Liu S, Liang H, Lee SM, et al. Isolation and identification of stem cells from degenerated human intervertebral discs and their migration characteristics. Acta Biochim Biophys Sin (Shanghai), 2017, 49(2): 101-109.
44. Risbud MV, Guttapalli A, Tsai TT, et al. Evidence for skeletal progenitor cells in the degenerate human intervertebral disc. Spine (Phila Pa 1976), 2007, 32(23): 2537-2544.
45. Sakai D, Nakamura Y, Nakai T, et al. Exhaustion of nucleus pulposus progenitor cells with ageing and degeneration of the intervertebral disc. Nat Commun, 2012, 3: 1264.
46. Yasen M, Fei Q, Hutton WC, et al. Changes of number of cells expressing proliferation and progenitor cell markers with age in rabbit intervertebral discs. Acta Biochim Biophys Sin (Shanghai), 2013, 45(5): 368-376.
47. Brisby H, Papadimitriou N, Brantsing C, et al. The presence of local mesenchymal progenitor cells in human degenerated intervertebral discs and possibilities to influence these in vitro: a descriptive study in humans. Stem Cells Dev, 2013, 22(5): 804-814.
48. Guan X, Ma X, Zhang L, et al. Evaluation of CD24 as a marker to rapidly define the mesenchymal stem cell phenotype and its differentiation in human nucleus pulposus. Chin Med J (Engl), 2014, 127(8): 1474-1481.
49. Peroglio M, Grad S, Mortisen D, et al. Injectable thermoreversible hyaluronan-based hydrogels for nucleus pulposus cell encapsulation. Eur Spine J, 2012, 21 Suppl 6: S839-849.

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