Korean J Pain.  2019 Oct;32(4):245-255. 10.3344/kjp.2019.32.4.245.

Stem cell therapy in pain medicine

• Han YH
• Kim KH
• Abdi S
• Kim TK

• KMID: 2462834
• DOI: http://doi.org/10.3344/kjp.2019.32.4.245

Abstract

Stem cells are attracting attention as a key element in future medicine, satisfying the desire to live a healthier life with the possibility that they can regenerate tissue damaged or degenerated by disease or aging. Stem cells are defined as undifferentiated cells that have the ability to replicate and differentiate themselves into various tissues cells. Stem cells, commonly encountered in clinical or preclinical stages, are largely classified into embryonic, adult, and induced pluripotent stem cells. Recently, stem cell transplantation has been frequently applied to the treatment of pain as an alternative or promising approach for the treatment of severe osteoarthritis, neuropathic pain, and intractable musculoskeletal pain which do not respond to conventional medicine. The main idea of applying stem cells to neuropathic pain is based on the ability of stem cells to release neurotrophic factors, along with providing a cellular source for replacing the injured neural cells, making them ideal candidates for modulating and possibly reversing intractable neuropathic pain. Even though various differentiation capacities of stem cells are reported, there is not enough knowledge and technique to control the differentiation into desired tissues in vivo. Even though the use of stem cells is still in the very early stages of clinical use and raises complicated ethical problems, the future of stem cells therapies is very bright with the help of accumulating evidence and technology.

Keyword

Adult Stem Cells; Aging; Cell Differentiation; Embryonic Stem Cells; Induced Pluripotent Stem Cells; Musculoskeletal Pain; Nerve Growth Factors; Neuralgia; Osteoarthritis

MeSH Terms

Adult
Adult Stem Cells
Aging
Cell Differentiation
Embryonic Stem Cells
Humans
Induced Pluripotent Stem Cells
Musculoskeletal Pain
Nerve Growth Factors
Neuralgia
Osteoarthritis
Stem Cell Transplantation
Stem Cells*
Nerve Growth Factors

Figure

• 

  Fig. 1 Three types of stem cells. After the sperm enters the ovum using the acrosome head to break the zona pellucida, the fertilized egg is called as a zygote before it divides into 16 cells (the morula). The blastocyst formation begins 5 days after fertilization. The blastocyst has 2 types of blastomere cells: the inner cell mass (embryoblast) and trophoblast. The inner cell mass becomes the embryo (till 8 wk), and then the fetus (from 9 wk). The embryonic stem cells are derived from the inner cell mass of the blastocyst. The induced pluripotent stem cells are made from the differentiated somatic cells of the adult, affected by Yamanaka factor. The adult stem cells vary from 1) the hematopoietic stem cells, derived from the umbilical cord of the fetus, 2) the bone marrow mesenchymal stem cells and hematopoietic stem cells, harvested from the bone marrow of an adult, 3) the adipose mesenchymal stem cells, derived from adipose tissue, and 4) the organ mesenchymal stem cells, harvested from the adult body. The embryonic and induced pluripotent stem cells have pluripotent potential; the adult stem cells have multipotent properties. Self-renewal ability, the malignancy rate, and the possibility of ethical problems are increasingly higher in the adult stem cells, induced pluripotent stem cells, and embryonic stem cells, respectively.

Reference

1. Thomas ED, Lochte HL Jr, Lu WC, Ferrebee JW. Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy. N Engl J Med. 1957; 257:491–6. DOI: 10.1056/NEJM195709122571102. PMID: 13464965.

2. Ciervo Y, Ning K, Jun X, Shaw PJ, Mead RJ. Advances, challenges and future directions for stem cell therapy in amyotrophic lateral sclerosis. Mol Neurodegener. 2017; 12:85. DOI: 10.1186/s13024-017-0227-3. PMID: 29132389. PMCID: PMC5683324.

3. Cacione DG, do Carmo Novaes F, Moreno DH. Stem cell therapy for treatment of thromboangiitis obliterans (Buerger’s disease). Cochrane Database Syst Rev. 2018; 10:CD012794.

4. Venkatesh K, Sen D. Mesenchymal stem cells as a source of dopaminergic neurons: a potential cell based therapy for parkinson’s disease. Curr Stem Cell Res Ther. 2017; 12:326–47. DOI: 10.2174/1574888X12666161114122059. PMID: 27842480.

5. Ichim TE, Solano F, Lara F, Paris E, Ugalde F, Rodriguez JP, et al. Feasibility of combination allogeneic stem cell therapy for spinal cord injury: a case report. Int Arch Med. 2010; 3:30. DOI: 10.1186/1755-7682-3-30. PMID: 21070647. PMCID: PMC2989319.

6. Pers YM, Ruiz M, Noël D, Jorgensen C. Mesenchymal stem cells for the management of inflammation in osteoarthritis: state of the art and perspectives. Osteoarthritis Cartilage. 2015; 23:2027–35. DOI: 10.1016/j.joca.2015.07.004. PMID: 26521749.

7. Chakravarthy K, Chen Y, He C, Christo PJ. Stem cell therapy for chronic pain management: review of uses, advances, and adverse effects. Pain Physician. 2017; 20:293–305. PMID: 28535552.

8. Hosseini M, Yousefifard M, Aziznejad H, Nasirinezhad F. The effect of bone marrow-derived mesenchymal stem cell transplantation on allodynia and hyperalgesia in neuropathic animals: a systematic review with meta-analysis. Biol Blood Marrow Transplant. 2015; 21:1537–44. DOI: 10.1016/j.bbmt.2015.05.008. PMID: 25985918.

9. Morrison SJ, Shah NM, Anderson DJ. Regulatory mechanisms in stem cell biology. Cell. 1997; 88:287–98. DOI: 10.1016/S0092-8674(00)81867-X. PMID: 9039255.

10. Blank U, Karlsson G, Karlsson S. Signaling pathways governing stem-cell fate. Blood. 2008; 111:492–503. DOI: 10.1182/blood-2007-07-075168. PMID: 17914027.

11. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, et al. Embryonic stem cell lines derived from human blastocysts. Science. 1998; 282:1145–7. DOI: 10.1126/science.282.5391.1145. PMID: 9804556.

12. Lagasse E, Connors H, Al-Dhalimy M, Reitsma M, Dohse M, Osborne L, et al. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat Med. 2000; 6:1229–34. DOI: 10.1038/81326. PMID: 11062533.

13. Kocher AA, Schuster MD, Szabolcs MJ, Takuma S, Burkhoff D, Wang J, et al. Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med. 2001; 7:430–6. DOI: 10.1038/86498. PMID: 11283669.

14. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006; 126:663–76. DOI: 10.1016/j.cell.2006.07.024. PMID: 16904174.

15. Ankrum JA, Ong JF, Karp JM. Mesenchymal stem cells: immune evasive, not immune privileged. Nat Biotechnol. 2014; 32:252–60. DOI: 10.1038/nbt.2816. PMID: 24561556. PMCID: PMC4320647.

16. Le Blanc K. Immunomodulatory effects of fetal and adult mesenchymal stem cells. Cytotherapy. 2003; 5:485–9. DOI: 10.1080/14653240310003611. PMID: 14660044.

17. Zakrzewski W, Dobrzyński M, Szymonowicz M, Rybak Z. Stem cells: past, present, and future. Stem Cell Res Ther. 2019; 10:68. DOI: 10.1186/s13287-019-1165-5. PMID: 30808416. PMCID: PMC6390367.

18. Chagastelles PC, Nardi NB. Biology of stem cells: an overview. Kidney Int Suppl (2011). 2011; 1:63–7. DOI: 10.1038/kisup.2011.15. PMID: 25028627. PMCID: PMC4089750.

19. Oh IH, Kim DW. Three-dimensional approach to stem cell therapy. J Korean Med Sci. 2002; 17:151–60. DOI: 10.3346/jkms.2002.17.2.151. PMID: 11961296. PMCID: PMC3054865.

20. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006; 8:315–7. DOI: 10.1080/14653240600855905. PMID: 16923606.

21. Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ, et al. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 2001; 7:211–28. DOI: 10.1089/107632701300062859. PMID: 11304456.

22. Gronthos S, Franklin DM, Leddy HA, Robey PG, Storms RW, Gimble JM. Surface protein characterization of human adipose tissue-derived stromal cells. J Cell Physiol. 2001; 189:54–63. DOI: 10.1002/jcp.1138. PMID: 11573204.

23. Aust L, Devlin B, Foster SJ, Halvorsen YD, Hicok K, du Laney T, et al. Yield of human adipose-derived adult stem cells from liposuction aspirates. Cytotherapy. 2004; 6:7–14. DOI: 10.1080/14653240310004539. PMID: 14985162.

24. Boquest AC, Shahdadfar A, Brinchmann JE, Collas P. Isolation of stromal stem cells from human adipose tissue. Methods Mol Biol. 2006; 325:35–46. PMID: 16761717.

25. Locke M, Windsor J, Dunbar PR. Human adipose-derived stem cells: isolation, characterization and applications in surgery. ANZ J Surg. 2009; 79:235–44. DOI: 10.1111/j.1445-2197.2009.04852.x. PMID: 19432707.

26. Safford KM, Rice HE. Stem cell therapy for neurologic disorders: therapeutic potential of adipose-derived stem cells. Curr Drug Targets. 2005; 6:57–62. DOI: 10.2174/1389450053345028. PMID: 15720213.

27. Prockop DJ. Marrow stromal cells as stem cells for nonhematopoietic tissues. Science. 1997; 276:71–4. DOI: 10.1126/science.276.5309.71. PMID: 9082988.

28. Majumdar MK, Banks V, Peluso DP, Morris EA. Isolation, characterization, and chondrogenic potential of human bone marrow-derived multipotential stromal cells. J Cell Physiol. 2000; 185:98–106. DOI: 10.1002/1097-4652(200010)185:1<98::AID-JCP9>3.0.CO;2-1. PMID: 10942523.

29. Johnstone B, Hering TM, Caplan AI, Goldberg VM, Yoo JU. In vitro chondrogenesis of bone marrow-derived mesenchymal progenitor cells. Exp Cell Res. 1998; 238:265–72. DOI: 10.1006/excr.1997.3858. PMID: 9457080.

30. Pers YM, Rackwitz L, Ferreira R, Pullig O, Delfour C, Barry F, et al. Adipose mesenchymal stromal cell-based therapy for severe osteoarthritis of the knee: a phase i dose-escalation trial. Stem Cells Transl Med. 2016; 5:847–56. DOI: 10.5966/sctm.2015-0245. PMID: 27217345. PMCID: PMC4922848.

31. Siniscalco D, Giordano C, Galderisi U, Luongo L, de Novellis V, Rossi F, et al. Long-lasting effects of human mesenchymal stem cell systemic administration on pain-like behaviors, cellular, and biomolecular modifications in neuropathic mice. Front Integr Neurosci. 2011; 5:79. DOI: 10.3389/fnint.2011.00079. PMID: 22164136. PMCID: PMC3230031.

32. Richardson SM, Kalamegam G, Pushparaj PN, Matta C, Memic A, Khademhosseini A, et al. Mesenchymal stem cells in regenerative medicine: focus on articular cartilage and intervertebral disc regeneration. Methods. 2016; 99:69–80. DOI: 10.1016/j.ymeth.2015.09.015. PMID: 26384579.

33. Migliorini F, Rath B, Tingart M, Baroncini A, Quack V, Eschweiler J. Autogenic mesenchymal stem cells for intervertebral disc regeneration. Int Orthop. 2019; 43:1027–36. DOI: 10.1007/s00264-018-4218-y. PMID: 30415465.

34. Li MH, Xiao R, Li JB, Zhu Q. Regenerative approaches for cartilage repair in the treatment of osteoarthritis. Osteoarthritis Cartilage. 2017; 25:1577–87. DOI: 10.1016/j.joca.2017.07.004. PMID: 28705606.

35. Brittberg M, Lindahl A, Nilsson A, Ohlsson C, Isaksson O, Peterson L. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med. 1994; 331:889–95. DOI: 10.1056/NEJM199410063311401. PMID: 8078550.

36. Yan H, Yu C. Repair of full-thickness cartilage defects with cells of different origin in a rabbit model. Arthroscopy. 2007; 23:178–87. DOI: 10.1016/j.arthro.2006.09.005. PMID: 17276226.

37. Goessler UR, Bugert P, Bieback K, Stern-Straeter J, Bran G, Hörmann K, et al. Integrin expression in stem cells from bone marrow and adipose tissue during chondrogenic differentiation. Int J Mol Med. 2008; 21:271–9. PMID: 18288373.

38. 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; 24:1294–301. DOI: 10.1634/stemcells.2005-0342. PMID: 16410387.

39. Wakitani S, Imoto K, Yamamoto T, Saito M, Murata N, Yoneda M. Human autologous culture expanded bone marrow mesenchymal cell transplantation for repair of cartilage defects in osteoarthritic knees. Osteoarthritis Cartilage. 2002; 10:199–206. DOI: 10.1053/joca.2001.0504. PMID: 11869080.

40. Wakitani S, Mitsuoka T, Nakamura N, Toritsuka Y, Nakamura Y, Horibe S. Autologous bone marrow stromal cell transplantation for repair of full-thickness articular cartilage defects in human patellae: two case reports. Cell Transplant. 2004; 13:595–600. DOI: 10.3727/000000004783983747. PMID: 15565871.

41. Wakitani S, Nawata M, Tensho K, Okabe T, Machida H, Ohgushi H. Repair of articular cartilage defects in the patellofemoral joint with autologous bone marrow mesenchymal cell transplantation: three case reports involving nine defects in five knees. J Tissue Eng Regen Med. 2007; 1:74–9. DOI: 10.1002/term.8. PMID: 18038395.

42. Erggelet C, Vavken P. Microfracture for the treatment of cartilage defects in the knee joint - a golden standard? J Clin Orthop Trauma. 2016; 7:145–52. DOI: 10.1016/j.jcot.2016.06.015. PMID: 27489408. PMCID: PMC4949407.

43. Kramer J, Böhrnsen F, Lindner U, Behrens P, Schlenke P, Rohwedel J. In vivo matrix-guided human mesenchymal stem cells. Cell Mol Life Sci. 2006; 63:616–26. DOI: 10.1007/s00018-005-5527-z. PMID: 16482398.

44. Tseng WJ, Huang SW, Fang CH, Hsu LT, Chen CY, Shen HH, et al. Treatment of osteoarthritis with collagen-based scaffold: a porcine animal model with xenograft mesenchymal stem cells. Histol Histopathol. 2018; 33:1271–86. PMID: 29905361.

45. Centeno CJ, Busse D, Kisiday J, Keohan C, Freeman M, Karli D. Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells. Pain Physician. 2008; 11:343–53. PMID: 18523506.

46. Varma HS, Dadarya B, Vidyarthi A. The new avenues in the management of osteo-arthritis of knee--stem cells. J Indian Med Assoc. 2010; 108:583–5. PMID: 21510531.

47. Levinger I, Levinger P, Trenerry MK, Feller JA, Bartlett JR, Bergman N, et al. Increased inflammatory cytokine expression in the vastus lateralis of patients with knee osteoarthritis. Arthritis Rheum. 2011; 63:1343–8. DOI: 10.1002/art.30287. PMID: 21538317.

48. Orita S, Koshi T, Mitsuka T, Miyagi M, Inoue G, Arai G, et al. Associations between proinflammatory cytokines in the synovial fluid and radiographic grading and pain-related scores in 47 consecutive patients with osteoarthritis of the knee. BMC Musculoskelet Disord. 2011; 12:144. DOI: 10.1186/1471-2474-12-144. PMID: 21714933. PMCID: PMC3144455.

49. Peeters CM, Leijs MJ, Reijman M, van Osch GJ, Bos PK. Safety of intra-articular cell-therapy with culture-expanded stem cells in humans: a systematic literature review. Osteoarthritis Cartilage. 2013; 21:1465–73. DOI: 10.1016/j.joca.2013.06.025. PMID: 23831631.

50. Centeno CJ, Schultz JR, Cheever M, Robinson B, Freeman M, Marasco W. Safety and complications reporting on the re-implantation of culture-expanded mesenchymal stem cells using autologous platelet lysate technique. Curr Stem Cell Res Ther. 2010; 5:81–93. DOI: 10.2174/157488810790442796. PMID: 19951252.

51. Kim SH, Ha CW, Park YB, Nam E, Lee JE, Lee HJ. Intraarticular injection of mesenchymal stem cells for clinical outcomes and cartilage repair in osteoarthritis of the knee: a meta-analysis of randomized controlled trials. Arch Orthop Trauma Surg. 2019; 139:971–80. DOI: 10.1007/s00402-019-03140-8. PMID: 30756165.

52. Ha CW, Park YB, Kim SH, Lee HJ. Intra-articular mesenchymal stem cells in osteoarthritis of the knee: a systematic review of clinical outcomes and evidence of cartilage repair. Arthroscopy. 2019; 35:277–88.e2. DOI: 10.1016/j.arthro.2018.07.028. PMID: 30455086.

53. Rodriguez-Merchan EC. Intra-articular injections of fatderived mesenchymal stem cells in knee osteoarthritis: are they recommended? Hosp Pract (1995). 2018; 46:172–4. DOI: 10.1080/21548331.2018.1505181. PMID: 30052101.

54. Pas HI, Winters M, Haisma HJ, Koenis MJ, Tol JL, Moen MH. Stem cell injections in knee osteoarthritis: a systematic review of the literature. Br J Sports Med. 2017; 51:1125–33. DOI: 10.1136/bjsports-2016-096793. PMID: 28258177.

55. Iijima H, Isho T, Kuroki H, Takahashi M, Aoyama T. Effectiveness of mesenchymal stem cells for treating patients with knee osteoarthritis: a meta-analysis toward the establishment of effective regenerative rehabilitation. NPJ Regen Med. 2018; 3:15. DOI: 10.1038/s41536-018-0041-8. PMID: 30245848. PMCID: PMC6141619.

56. Hofstetter CP, Holmström NA, Lilja JA, Schweinhardt P, Hao J, Spenger C, et al. Allodynia limits the usefulness of intraspinal neural stem cell grafts; directed differentiation improves outcome. Nat Neurosci. 2005; 8:346–53. DOI: 10.1038/nn1405. PMID: 15711542.

57. Fischer UM, Harting MT, Jimenez F, Monzon-Posadas WO, Xue H, Savitz SI, et al. Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary firstpass effect. Stem Cells Dev. 2009; 18:683–92. DOI: 10.1089/scd.2008.0253. PMID: 19099374. PMCID: PMC3190292.

58. Lu D, Mahmood A, Wang L, Li Y, Lu M, Chopp M. Adult bone marrow stromal cells administered intravenously to rats after traumatic brain injury migrate into brain and improve neurological outcome. Neuroreport. 2001; 12:559–63. DOI: 10.1097/00001756-200103050-00025. PMID: 11234763.

59. Zhang J, Shi XQ, Echeverry S, Mogil JS, De Koninck Y, Rivest S. Expression of CCR2 in both resident and bone marrow-derived microglia plays a critical role in neuropathic pain. J Neurosci. 2007; 27:12396–406. DOI: 10.1523/JNEUROSCI.3016-07.2007. PMID: 17989304. PMCID: PMC6673247.

60. Mahmood A, Lu D, Chopp M. Intravenous administration of marrow stromal cells (MSCs) increases the expression of growth factors in rat brain after traumatic brain injury. J Neurotrauma. 2004; 21:33–9. DOI: 10.1089/089771504772695922. PMID: 14987463.

61. Siniscalco D, Giordano C, Galderisi U, Luongo L, Alessio N, Di Bernardo G, et al. Intra-brain microinjection of human mesenchymal stem cells decreases allodynia in neuropathic mice. Cell Mol Life Sci. 2010; 67:655–69. DOI: 10.1007/s00018-009-0202-4. PMID: 19937263.

62. Chen G, Park CK, Xie RG, Ji RR. Intrathecal bone marrow stromal cells inhibit neuropathic pain via TGF-β secretion. J Clin Invest. 2015; 125:3226–40. DOI: 10.1172/JCI80883. PMID: 26168219. PMCID: PMC4563753.

63. Mariani E, Facchini A. Clinical applications and biosafety of human adult mesenchymal stem cells. Curr Pharm Des. 2012; 18:1821–45. DOI: 10.2174/138161212799859666. PMID: 22352750.

64. Nesti C, Pardini C, Barachini S, D’Alessandro D, Siciliano G, Murri L, et al. Human dental pulp stem cells protect mouse dopaminergic neurons against MPP+ or rotenone. Brain Res. 2011; 1367:94–102. DOI: 10.1016/j.brainres.2010.09.042. PMID: 20854799.

65. Sarnowska A, Braun H, Sauerzweig S, Reymann KG. The neuroprotective effect of bone marrow stem cells is not dependent on direct cell contact with hypoxic injured tissue. Exp Neurol. 2009; 215:317–27. DOI: 10.1016/j.expneurol.2008.10.023. PMID: 19063882.

66. Ossipov MH. Growth factors and neuropathic pain. Curr Pain Headache Rep. 2011; 15:185–92. DOI: 10.1007/s11916-011-0183-5. PMID: 21327569.

67. Scholz J, Woolf CJ. The neuropathic pain triad: neurons, immune cells and glia. Nat Neurosci. 2007; 10:1361–8. DOI: 10.1038/nn1992. PMID: 17965656.

68. Martucci C, Trovato AE, Costa B, Borsani E, Franchi S, Magnaghi V, et al. The purinergic antagonist PPADS reduces pain related behaviours and interleukin-1 beta, interleukin-6, iNOS and nNOS overproduction in central and peripheral nervous system after peripheral neuropathy in mice. Pain. 2008; 137:81–95. DOI: 10.1016/j.pain.2007.08.017. PMID: 17900807.

69. Apfel SC. Neurotrophic factors in peripheral neuropathies: therapeutic implications. Brain Pathol. 1999; 9:393–413. DOI: 10.1111/j.1750-3639.1999.tb00234.x. PMID: 10219753.

70. Alexander GM, van Rijn MA, van Hilten JJ, Perreault MJ, Schwartzman RJ. Changes in cerebrospinal fluid levels of pro-inflammatory cytokines in CRPS. Pain. 2005; 116:213–9. DOI: 10.1016/j.pain.2005.04.013. PMID: 15964681.

71. Cova L, Armentero MT, Zennaro E, Calzarossa C, Bossolasco P, Busca G, et al. Multiple neurogenic and neurorescue effects of human mesenchymal stem cell after transplantation in an experimental model of Parkinson’s disease. Brain Res. 2010; 1311:12–27. DOI: 10.1016/j.brainres.2009.11.041. PMID: 19945443.

72. Koh SH, Kim KS, Choi MR, Jung KH, Park KS, Chai YG, et al. Implantation of human umbilical cord-derived mesenchymal stem cells as a neuroprotective therapy for ischemic stroke in rats. Brain Res. 2008; 1229:233–48. DOI: 10.1016/j.brainres.2008.06.087. PMID: 18634757.

73. Reid AJ, Sun M, Wiberg M, Downes S, Terenghi G, Kingham PJ. Nerve repair with adipose-derived stem cells protects dorsal root ganglia neurons from apoptosis. Neuroscience. 2011; 199:515–22. DOI: 10.1016/j.neuroscience.2011.09.064. PMID: 22020320.

74. Park HJ, Lee PH, Bang OY, Lee G, Ahn YH. Mesenchymal stem cells therapy exerts neuroprotection in a progressive animal model of Parkinson’s disease. J Neurochem. 2008; 107:141–51. DOI: 10.1111/j.1471-4159.2008.05589.x. PMID: 18665911.

75. Edalatmanesh MA, Bahrami AR, Hosseini E, Hosseini M, Khatamsaz S. Neuroprotective effects of mesenchymal stem cell transplantation in animal model of cerebellar degeneration. Neurol Res. 2011; 33:913–20. DOI: 10.1179/1743132811Y.0000000036. PMID: 22080991.

76. Meirelles Lda S, Fontes AM, Covas DT, Caplan AI. Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine Growth Factor Rev. 2009; 20:419–27. DOI: 10.1016/j.cytogfr.2009.10.002. PMID: 19926330.

77. Ghannam S, Bouffi C, Djouad F, Jorgensen C, Noël D. Immunosuppression by mesenchymal stem cells: mechanisms and clinical applications. Stem Cell Res Ther. 2010; 1:2. DOI: 10.1186/scrt2. PMID: 20504283. PMCID: PMC2873698.

78. Zhang EJ, Song CH, Ko YK, Lee WH. Intrathecal administration of mesenchymal stem cells reduces the reactive oxygen species and pain behavior in neuropathic rats. Korean J Pain. 2014; 27:239–45. DOI: 10.3344/kjp.2014.27.3.239. PMID: 25031809. PMCID: PMC4099236.

79. Jeong JO, Kim MO, Kim H, Lee MY, Kim SW, Ii M, et al. Dual angiogenic and neurotrophic effects of bone marrow-derived endothelial progenitor cells on diabetic neuropathy. Circulation. 2009; 119:699–708. DOI: 10.1161/CIRCULATIONAHA.108.789297. PMID: 19171856. PMCID: PMC2746559.

80. Naruse K, Sato J, Funakubo M, Hata M, Nakamura N, Kobayashi Y, et al. Transplantation of bone marrow-derived mononuclear cells improves mechanical hyperalgesia, cold allodynia and nerve function in diabetic neuropathy. PLoS One. 2011; 6:e27458. DOI: 10.1371/journal.pone.0027458. PMID: 22125614. PMCID: PMC3220696.

81. Anitha M, Gondha C, Sutliff R, Parsadanian A, Mwangi S, Sitaraman SV, et al. GDNF rescues hyperglycemia-induced diabetic enteric neuropathy through activation of the PI3K/ Akt pathway. J Clin Invest. 2006; 116:344–56. DOI: 10.1172/JCI26295. PMID: 16453021. PMCID: PMC1359053.

82. Tse HF, Siu CW, Zhu SG, Songyan L, Zhang QY, Lai WH, et al. Paracrine effects of direct intramyocardial implantation of bone marrow derived cells to enhance neovascularization in chronic ischaemic myocardium. Eur J Heart Fail. 2007; 9:747–53. DOI: 10.1016/j.ejheart.2007.03.008. PMID: 17481945.

83. Shibata T, Naruse K, Kamiya H, Kozakae M, Kondo M, Yasuda Y, et al. Transplantation of bone marrow-derived mesenchymal stem cells improves diabetic polyneuropathy in rats. Diabetes. 2008; 57:3099–107. DOI: 10.2337/db08-0031. PMID: 18728233. PMCID: PMC2570407.

84. Kim BJ, Jin HK, Bae JS. Bone marrow-derived mesenchymal stem cells improve the functioning of neurotrophic factors in a mouse model of diabetic neuropathy. Lab Anim Res. 2011; 27:171–6. DOI: 10.5625/lar.2011.27.2.171. PMID: 21826178. PMCID: PMC3146005.

85. Waterman RS, Tomchuck SL, Henkle SL, Betancourt AM. A new mesenchymal stem cell (MSC) paradigm: polarization into a pro-inflammatory MSC1 or an immunosuppressive MSC2 phenotype. PLoS One. 2010; 5:e10088. DOI: 10.1371/journal.pone.0010088. PMID: 20436665. PMCID: PMC2859930.

86. Waterman RS, Morgenweck J, Nossaman BD, Scandurro AE, Scandurro SA, Betancourt AM. Anti-inflammatory mesenchymal stem cells (MSC2) attenuate symptoms of painful diabetic peripheral neuropathy. Stem Cells Transl Med. 2012; 1:557–65. DOI: 10.5966/sctm.2012-0025. PMID: 23197860. PMCID: PMC3659725.

87. Comerota AJ, Link A, Douville J, Burchardt ER. Upper extremity ischemia treated with tissue repair cells from adult bone marrow. J Vasc Surg. 2010; 52:723–9. DOI: 10.1016/j.jvs.2010.04.020. PMID: 20576396.

88. Yezierski RP. Pain following spinal cord injury: the clinical problem and experimental studies. Pain. 1996; 68:185–94. DOI: 10.1016/S0304-3959(96)03178-8. PMID: 9121805.

89. Satake K, Matsuyama Y, Kamiya M, Kawakami H, Iwata H, Adachi K, et al. Up-regulation of glial cell line-derived neurotrophic factor (GDNF) following traumatic spinal cord injury. Neuroreport. 2000; 11:3877–81. DOI: 10.1097/00001756-200011270-00054. PMID: 11117507.

90. Schnell L, Schneider R, Kolbeck R, Barde YA, Schwab ME. Neurotrophin-3 enhances sprouting of corticospinal tract during development and after adult spinal cord lesion. Nature. 1994; 367:170–3. DOI: 10.1038/367170a0. PMID: 8114912.

91. Eaton MJ, Wolfe SQ, Martinez M, Hernandez M, Furst C, Huang J, et al. Subarachnoid transplant of a human neuronal cell line attenuates chronic allodynia and hyperalgesia after excitotoxic spinal cord injury in the rat. J Pain. 2007; 8:33–50. DOI: 10.1016/j.jpain.2006.05.013. PMID: 17207742.

92. Hofstetter CP, Schwarz EJ, Hess D, Widenfalk J, El Manira A, Prockop DJ, et al. Marrow stromal cells form guiding strands in the injured spinal cord and promote recovery. Proc Natl Acad Sci U S A. 2002; 99:2199–204. DOI: 10.1073/pnas.042678299. PMID: 11854516. PMCID: PMC122342.

93. Yang CC, Shih YH, Ko MH, Hsu SY, Cheng H, Fu YS. Transplantation of human umbilical mesenchymal stem cells from Wharton’s jelly after complete transection of the rat spinal cord. PLoS One. 2008; 3:e3336. DOI: 10.1371/journal.pone.0003336. PMID: 18852872. PMCID: PMC2566594.

94. Yousefifard M, Rahimi-Movaghar V, Nasirinezhad F, Baikpour M, Safari S, Saadat S, et al. Neural stem/progenitor cell transplantation for spinal cord injury treatment; a systematic review and meta-analysis. Neuroscience. 2016; 322:377–97. DOI: 10.1016/j.neuroscience.2016.02.034. PMID: 26917272.

95. Macias MY, Syring MB, Pizzi MA, Crowe MJ, Alexanian AR, Kurpad SN. Pain with no gain: allodynia following neural stem cell transplantation in spinal cord injury. Exp Neurol. 2006; 201:335–48. DOI: 10.1016/j.expneurol.2006.04.035. PMID: 16839548.

96. Klass M, Gavrikov V, Drury D, Stewart B, Hunter S, Denson DD, et al. Intravenous mononuclear marrow cells reverse neuropathic pain from experimental mononeuropathy. Anesth Analg. 2007; 104:944–8. DOI: 10.1213/01.ane.0000258021.03211.d0. PMID: 17377111.

97. Vadivelu S, Willsey M, Curry DJ, McDonald JW 3rd. Potential role of stem cells for neuropathic pain disorders. Neurosurg Focus. 2013; 35:E11. DOI: 10.3171/2013.6.FOCUS13235. PMID: 23991814.

98. Choi JI, Cho HT, Jee MK, Kang SK. Core-shell nanoparticle controlled hATSCs neurogenesis for neuropathic pain therapy. Biomaterials. 2013; 34:4956–70. DOI: 10.1016/j.biomaterials.2013.02.037. PMID: 23582861.

99. Franchi S, Valsecchi AE, Borsani E, Procacci P, Ferrari D, Zalfa C, et al. Intravenous neural stem cells abolish nociceptive hypersensitivity and trigger nerve regeneration in experimental neuropathy. Pain. 2012; 153:850–61. DOI: 10.1016/j.pain.2012.01.008. PMID: 22321918.

100. Sacerdote P, Niada S, Franchi S, Arrigoni E, Rossi A, Yenagi V, et al. Systemic administration of human adipose-derived stem cells reverts nociceptive hypersensitivity in an experimental model of neuropathy. Stem Cells Dev. 2013; 22:1252–63. DOI: 10.1089/scd.2012.0398. PMID: 23190263. PMCID: PMC3613970.

101. Coronel MF, Musolino PL, Brumovsky PR, Hökfelt T, Villar MJ. Bone marrow stromal cells attenuate injury-induced changes in galanin, NPY and NPY Y1-receptor expression after a sciatic nerve constriction. Neuropeptides. 2009; 43:125–32. DOI: 10.1016/j.npep.2008.12.003. PMID: 19168218.

102. Lee S, Moon CS, Sul D, Lee J, Bae M, Hong Y, et al. Comparison of growth factor and cytokine expression in patients with degenerated disc disease and herniated nucleus pulposus. Clin Biochem. 2009; 42:1504–11. DOI: 10.1016/j.clinbiochem.2009.06.017. PMID: 19563795.

103. Orozco L, Soler R, Morera C, Alberca M, Sánchez A, García-Sancho J. Intervertebral disc repair by autologous mesenchymal bone marrow cells: a pilot study. Transplantation. 2011; 92:822–8. DOI: 10.1097/TP.0b013e3182298a15. PMID: 21792091.

104. Franchi S, Castelli M, Amodeo G, Niada S, Ferrari D, Vescovi A, et al. Adult stem cell as new advanced therapy for experimental neuropathic pain treatment. Biomed Res Int. 2014; 2014:470983. DOI: 10.1155/2014/470983. PMID: 25197647. PMCID: PMC4147203.

105. Ikebe C, Suzuki K. Mesenchymal stem cells for regenerative therapy: optimization of cell preparation protocols. Biomed Res Int. 2014; 2014:951512. DOI: 10.1155/2014/951512.

106. Koga H, Engebretsen L, Brinchmann JE, Muneta T, Sekiya I. Mesenchymal stem cell-based therapy for cartilage repair: a review. Knee Surg Sports Traumatol Arthrosc. 2009; 17:1289–97. DOI: 10.1007/s00167-009-0782-4. PMID: 19333576.

107. Van Osch GJ, Van Der Veen SW, Burger EH, Verwoerd-Verhoef HL. Chondrogenic potential of in vitro multiplied rabbit perichondrium cells cultured in alginate beads in defined medium. Tissue Eng. 2000; 6:321–30. DOI: 10.1089/107632700418047. PMID: 10992429.

108. Wiesmann A, Bühring HJ, Mentrup C, Wiesmann HP. Decreased CD90 expression in human mesenchymal stem cells by applying mechanical stimulation. Head Face Med. 2006; 2:8. DOI: 10.1186/1746-160X-2-8. PMID: 16573842. PMCID: PMC1483821.