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Published Online: 22 July 2014

A Systematic Review of the Safety and Efficacy of Mesenchymal Stem Cells for Disc Degeneration: Insights and Future Directions for Regenerative Therapeutics

Publication: Stem Cells and Development
Volume 23, Issue Number 21


Intervertebral disc degeneration is associated with low-back pain. Mesenchymal stem cells (MSCs) have been used to “regenerate” the disc. The aim of this study was to perform a systematic review of comparative controlled studies that have assessed the safety and efficacy of using MSCs for disc regeneration. Literature databases were extensively searched. Trial design, subject-type, MSC sources, injection method, disc assessment, outcome intervals, and complication events were assessed. Validity of each study was performed. Twenty-four animal studies were included with 20.8% of the studies reporting randomization of groups. Trials in humans fulfilling inclusion criteria were not noted. The studies represented 862 discs that were injected with MSCs and 1,603 discs as controls. All three types of MSCs (ie, bone marrow, synovial, and adipose tissues) showed successful inhibition of disc degeneration. Bone-marrow-derived MSCs demonstrated superior quality of repair compared with other non-MSC treatments. A 2.7% overall complication rate was noted, whereby complications were noted only in rabbits. Overall, evidence suggested that MSCs increased disc space height in the majority of animal models. This is the first systematic review to assess the safety and efficacy of MSCs for the treatment of disc degeneration. Short-term MSC transplantation is safe and effective; however, additional, larger, and higher-quality studies are needed to assess the long-term safety and efficacy. Inconsistencies in methodological design and outcome parameters prevent any robust conclusions. Human-based clinical trials are needed. Recommendations are further made to improve efficacy, reduce potential complications, and standardize techniques for future studies.

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Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati M, Shibuya K, Salomon JA, Abdalla S, et al. (2012). Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380:2163–2196.
Deyo RA and Tsui-Wu YJ. (1987). Descriptive epidemiology of low-back pain and its related medical care in the United States. Spine (Phila Pa 1976) 12:264–268.
Karppinen J, Shen FH, Luk KD, Andersson GB, Cheung KM and Samartzis D. (2011). Management of degenerative disk disease and chronic low back pain. Orthop Clin North Am 42:513–528, viii.
Shen FH, Samartzis D and Andersson GB. (2006). Nonsurgical management of acute and chronic low back pain. J Am Acad Orthop Surg 14:477–487.
Cheung KM, Karppinen J, Chan D, Ho DW, Song YQ, Sham P, Cheah KS, Leong JC and Luk KD. (2009). Prevalence and pattern of lumbar magnetic resonance imaging changes in a population study of one thousand forty-three individuals. Spine (Phila Pa 1976) 34:934–940.
de Schepper EI, Damen J, van Meurs JB, Ginai AZ, Popham M, Hofman A, Koes BW and Bierma-Zeinstra SM. (2010). The association between lumbar disc degeneration and low back pain: the influence of age, gender, and individual radiographic features. Spine (Phila Pa 1976) 35:531–536.
Samartzis D, Karppinen J, Chan D, Luk KD and Cheung. KM (2010). The association of disc degeneration based on magnetic resonance imaging and the presence of low back pain. In: World Forum for Spine Research: Intervertebral Disc. Montreal, Canada.
Samartzis D, Karppinen J, Mok F, Fong DY, Luk KD and Cheung KM. (2011). 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 93:662–670.
Takatalo J, Karppinen J, Niinimäki J, Taimela S, Näyhä S, Mutanen P, Sequeiros RB, Kyllönen E and Tervonen O. (2011). Does lumbar disc degeneration on MRI associate with low back symptom severity in young Finnish adults?. Spine (Phila Pa 1976) 36:2180–2189.
Kjaer P, Leboeuf-Yde C, Korsholm L, Sorensen JS and Bendix T. (2005). Magnetic resonance imaging and low back pain in adults: a diagnostic imaging study of 40-year-old men and women. Spine (Phila Pa 1976) 30:1173–1180.
Visuri T, Ulaska J, Eskelin M and Pulkkinen P. (2005). Narrowing of lumbar spinal canal predicts chronic low back pain more accurately than intervertebral disc degeneration: a magnetic resonance imaging study in young Finnish male conscripts. Mil Med 170:926–930.
Paajanen H, Erkintalo M, Kuusela T, Dahlstrom S and Kormano M. (1989). Magnetic resonance study of disc degeneration in young low-back pain patients. Spine (Phila Pa 1976) 14:982–985.
Paajanen H, Erkintalo M, Parkkola R, Salminen J and Kormano M. (1997). Age-dependent correlation of low-back pain and lumbar disc regeneration. Arch Orthop Trauma Surg 116:106–107.
Chou D, Samartzis D, Bellabarba C, Patel A, Luk KDK, Schenk-Kisser JM and Skelly AC. (2011). Degenerative MRI findings in patients with chronic low back pain: a systematic review. Spine (Phila Pa 1976) 36:S43–S53.
Adams MA, Freeman BJ, Morrison HP, Nelson IW and Dolan P. (2000). Mechanical initiation of intervertebral disc degeneration. Spine (Phila Pa 1976) 25:1625–1636.
Urban JP and McMullin JF. (1988). Swelling pressure of the lumbar intervertebral discs: influence of age, spinal level, composition, and degeneration. Spine (Phila Pa 1976) 13:179–187.
Biyani A and Andersson GBJ. (2004). Low back pain: pathophysiology and management. J Am Acad Orthop Surg 12:106–115.
Adams MA and Roughley PJ. (2006). What is intervertebral disc degeneration, and what causes it?. Spine (Phila Pa 1976) 31:2151–2161.
Urban JP, Holm S, Maroudas A and Nachemson A. (1982). Nutrition of the intervertebral disc: effect of fluid flow on solute transport. Clin Orthop Relat Res:296–302.
Urban JP and Roberts S. (2003). Degeneration of the intervertebral disc. Arthritis Res Ther 5:120–130.
Urban JP and Winlove CP. (2007). Pathophysiology of the intervertebral disc and the challenges for MRI. J Magn Reson Imaging 25:419–432.
Fujiwara A, An HS, Lim TH and Haughton VM. (2001). Morphologic changes in the lumbar intervertebral foramen due to flexion-extension, lateral bending, and axial rotation: an in vitro anatomic and biomechanical study. Spine (Phila Pa 1976) 26:876–882.
Fujiwara A, Tamai K, An HS, Kurihashi T, Lim TH, Yoshida H and Saotome K. (2000). The relationship between disc degeneration, facet joint osteoarthritis, and stability of the degenerative lumbar spine. J Spinal Disord 13:444–450.
Fujiwara A, Tamai K, Yamato M, An HS, Yoshida H, Saotome K and Kurihashi A. (1999). The relationship between facet joint osteoarthritis and disc degeneration of the lumbar spine: an MRI study. Eur Spine J 8:396–401.
Siepe CJ, Heider F, Wiechert K, Hitzl W, Ishak B and Mayer MH. (2014). Mid- to long-term results of total lumbar disc replacement: a prospective analysis with 5- to 10-year follow-up. Spine J..
Mannion AF, Brox JI and Fairbank JC. (2013). Comparison of spinal fusion and nonoperative treatment in patients with chronic low back pain: long-term follow-up of three randomized controlled trials. Spine J 13:1438–1448.
Punt IM, Visser VM, van Rhijn LW, Kurtz SM, Antonis J, Schurink GW and van Ooij A. (2008). Complications and reoperations of the SB Charite lumbar disc prosthesis: experience in 75 patients. Eur Spine J 17:36–43.
An HS, Takegami K, Kamada H, Nguyen CM, Thonar EJ, Singh K, Andersson GB and Masuda K. (2005). Intradiscal administration of osteogenic protein-1 increases intervertebral disc height and proteoglycan content in the nucleus pulposus in normal adolescent rabbits. Spine (Phila Pa 1976) 30:25–31; discussion 31–32.
Bae WC and Masuda K. (2011). Emerging technologies for molecular therapy for intervertebral disk degeneration. Orthop Clin North Am 42:585–601, ix.
Masuda K, Oegema TR Jr. and An HS. (2004). Growth factors and treatment of intervertebral disc degeneration. Spine (Phila Pa 1976) 29:2757–2769.
Masuda K. (2008). Biological repair of the degenerated intervertebral disc by the injection of growth factors. Eur Spine J 17 Suppl 4:441–451.
Meisel HJ, Siodla V, Ganey T, Minkus Y, Hutton WC and Alasevic OJ. (2007). Clinical experience in cell-based therapeutics: disc chondrocyte transplantation A treatment for degenerated or damaged intervertebral disc. Biomol Eng 24:5–21.
Yoon ST and Patel NM. (2006). Molecular therapy of the intervertebral disc. Eur Spine J 15 Suppl 3:S379–S388.
Woods BI, Vo N, Sowa G and Kang JD. (2011). Gene therapy for intervertebral disk degeneration. Orthop Clin North Am 42:563–574, ix.
Orozco L, Soler R, Morera C, Alberca M, Sanchez A and Garcia-Sancho J. (2011). Intervertebral disc repair by autologous mesenchymal bone marrow cells: a pilot study. Transplantation 92:822–828.
Yoshikawa TMD, Ueda YMD, Miyazaki KMD, Koizumi MMD and Takakura YMD. (2010). Disc regeneration therapy using marrow mesenchymal cell transplantation: a report of two case studies. Spine (Phila Pa 1976) 35:E475–E480.
Zhang Y-G, Guo X, Xu P, Kang L-L and Li J. (2005). Bone mesenchymal stem cells transplanted into rabbit intervertebral discs can increase proteoglycans. Clin Orthop Relat Res 430:219–226.
Chou AI, Reza AT and Nicoll SB. (2008). Distinct intervertebral disc cell populations adopt similar phenotypes in three-dimensional culture. Tissue Eng Part A 14:2079–2087.
Leung V, Chan D and Cheung K. (2006). Regeneration of intervertebral disc by mesenchymal stem cells: potentials, limitations, and future direction. Eur Spine J 15:406–413.
Jeong J, Lee J, Jin E, Min J, Jeon S and Choi K. (2010). Regeneration of intervertebral discs in a rat disc degeneration model by implanted adipose-tissue-derived stromal cells. Acta Neurochir (Wien) 152:1771–1777.
Rovira J, Cid J, Gutierrez-Garcia G, Pereira A, Fernandez-Aviles F, Rosinol L, Martinez C, Carreras E, Urbano A, Rovira M and Lozano M. (2013). Fatal immune hemolytic anemia following allogeneic stem cell transplantation: report of 2 cases and review of literature. Transfus Med Rev 27:166–170.
Vadalà G, Sowa G, Hubert M, Gilbertson LG, Denaro V and Kang JD. (2011). Mesenchymal stem cells injection in degenerated intervertebral disc: cell leakage may induce osteophyte formation. J Tissue Eng Regen Med 6:348–355.
Amariglio N, Hirshberg A, Scheithauer BW, Cohen Y, Loewenthal R, Trakhtenbrot L, Paz N, Koren-Michowitz M, Waldman D and Leider-Trejo L. (2009). Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient. PLoS Med 6:e1000029
Moher D, Liberati A, Tetzlaff J and Altman DG. (2009). Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg 8:339–341.
Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJM, Gavaghan DJ and McQuay HJ. (1996). Assessing the quality of reports of randomized clinical trials: is blinding necessary?. Control Clin Trials 17:1–12.
Hee HT, Ismail HD, Lim CT, Goh JCH and Wong HK. (2010). Effects of implantation of bone marrow mesenchymal stem cells, disc distraction and combined therapy on reversing degeneration of the intervertebral disc. J Bone Joint Surg Br 92-B:726–736.
Bendtsen M, Bünger CE, Zou X, Foldager C and Jørgensen HS. (2011). Autologous stem cell therapy maintains vertebral blood flow and contrast diffusion through the endplate in experimental intervertebral disc degeneration. Spine (Phila Pa 1976) 36:E373–E379.
Crevensten G, Walsh AJL, Ananthakrishnan D, Page P, Wahba GM, Lotz JC and Berven S. (2004). Intervertebral disc cell therapy for regeneration: mesenchymal stem cell implantation in rat intervertebral discs. Ann Biomed Eng 32:430–434.
Yang F, Leung VYL, Luk KDK, Chan D and Cheung KMC. (2009). Mesenchymal stem cells arrest intervertebral disc degeneration through chondrocytic differentiation and stimulation of endogenous cells. Mol Ther 17:1959–1966.
Jeong J, Jin E, Min J, Jeon S, Park C-S, Kim H and Choi K. (2009). Human mesenchymal stem cells implantation into the degenerated coccygeal disc of the rat. Cytotechnology 59:55–64.
Allon AA, Aurouer N, Yoo BB, Liebenberg EC, Buser Z and Lotz JC. (2010). Structured coculture of stem cells and disc cells prevent disc degeneration in a rat model. Spine J 10:1089–1097.
Wei A, Tao H, Chung SA, Brisby H, Ma DD and Diwan AD. (2009). The fate of transplanted xenogeneic bone marrow-derived stem cells in rat intervertebral discs. J Orthop Res 27:374–379.
Feng G, Zhao X, Liu H, Zhang H, Chen X, Shi R, Liu X, Zhao X, Zhang W and Wang B. (2011). 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 14:322–329.
Sakai D, Mochida J, Iwashina T, Hiyama A, Omi H, Imai M, Nakai T, Ando K and Hotta T. (2006). Regenerative effects of transplanting mesenchymal stem cells embedded in atelocollagen to the degenerated intervertebral disc. Biomaterials 27:335–345.
Sakai D, Mochida J, Yamamoto Y, Nomura T, Okuma M, Nishimura K, Nakai T, Ando K and Hotta T. (2003). Transplantation of mesenchymal stem cells embedded in Atelocollagen® gel to the intervertebral disc: a potential therapeutic model for disc degeneration. Biomaterials 24:3531–3541.
Sakai DMD, Mochida JMD, Iwashina TMD, Watanabe TMD, Nakai T, Ando KMD and Hotta TMD. (2005). Differentiation of mesenchymal stem cells transplanted to a rabbit degenerative disc model: potential and limitations for stem cell therapy in disc regeneration. Spine (Phila Pa 1976) 30:2379–2387.
Ho G, Leung VYL, Cheung KMC and Chan D. (2008). Effect of severity of intervertebral disc injury on mesenchymal stem cell-based regeneration. Connect Tissue Res 49:15–21.
Sobajima S, Vadala G, Shimer A, Kim JS, Gilbertson LG and Kang JD. (2008). Feasibility of a stem cell therapy for intervertebral disc degeneration. Spine J 8:888–896.
Yang H, Wu J, Liu J, Ebraheim M, Castillo S, Liu X, Tang T and Ebraheim NA. (2010). Transplanted mesenchymal stem cells with pure fibrinous gelatin-transforming growth factor-[beta]1 decrease rabbit intervertebral disc degeneration. Spine J 10:802–810.
Serigano K, Sakai D, Hiyama A, Tamura F, Tanaka M and Mochida J. (2010). Effect of cell number on mesenchymal stem cell transplantation in a canine disc degeneration model. J Orthop Res 28:1267–1275.
Henriksson HBM, Svanvik TMD, Jonsson MLMS, Hagman MB, Horn MP, Lindahl AMDP and Brisby HMDP. (2009). Transplantation of human mesenchymal stems cells into intervertebral discs in a xenogeneic porcine model. Spine (Phila Pa 1976) 34:141–148.
Acosta F, Metz L, Adkisson H, Liu J, Carruthers-Liebenberg E, Milliman C, Maloney M and Lotz J. (2011). Porcine intervertebral disc repair using allogeneic juvenile articular chondrocytes or mesenchymal stem cells. Tissue Eng Part A 17:3045–3055.
Hiyama A, Mochida J, Iwashina T, Omi H, Watanabe T, Serigano K, Tamura F and Sakai D. (2008). Transplantation of mesenchymal stem cells in a canine disc degeneration model. J Orthop Res 26:589–600.
Ghosh P, Moore R, Vernon-Roberts B, Goldschlager T, Pascoe D, Zannettino A, Gronthos S and Itescu S. (2012). Immunoselected STRO-3+ mesenchymal precursor cells and restoration of the extracellular matrix of degenerate intervertebral discs. J Neurosurg Spine 16:479–488.
Ganey TP, Hutton WCD, Moseley TP, Hedrick MMD and Meisel H-JMDP. (2009). Intervertebral disc repair using adipose tissue-derived stem and regenerative cells: experiments in a canine model. Spine (Phila Pa 1976) 34:2297–2304.
Miyamoto T, Muneta T, Tabuchi T, Matsumoto K, Saito H, Tsuji K and Sekiya I. (2010). 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 12:R206
Song M, Heo J, Chun J-Y, Bae HS, Kang JW, Kang H, Cho YM, Kim SW, Shin D-M and Choo M-S. (2013). The paracrine effects of mesenchymal stem cells stimulate the regeneration capacity of endogenous stem cells in the repair of a bladder-outlet-obstruction-induced overactive bladder. Stem CellsDev 23:654–663.
Smith LJ, Nerurkar NL, Choi K-S, Harfe BD and Elliott DM. (2011). Degeneration and regeneration of the intervertebral disc: lessons from development. Dis Model Mech 4:31–41.
Risbud MV, Schaer TP and Shapiro IM. (2010). Toward an understanding of the role of notochordal cells in the adult intervertebral disc: from discord to accord. Dev Dyn 239:2141–2148.
Chen J, Yan W and Setton L. (2006). Molecular phenotypes of notochordal cells purified from immature nucleus pulposus. Eur Spine J 15:303–311.
Bergknut NP, Rutges JPHJMDP, Kranenburg H-JCDVM, Smolders LAB, Hagman RP, Smidt H-JB, Lagerstedt A-SDVMP, Penning LCP, Voorhout GDVMP, et al. (2012). The dog as an animal model for intervertebral disc degeneration?. Spine (Phila Pa 1976) 37:351–358.

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Published In

cover image Stem Cells and Development
Stem Cells and Development
Volume 23Issue Number 21November 1, 2014
Pages: 2553 - 2567
PubMed: 25050446


Published in print: November 1, 2014
Published ahead of print: 11 September 2014
Published online: 22 July 2014
Accepted: 22 July 2014
Received: 27 April 2014


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Rita Lok-Hay Yim
Department of Orthopaedics and Traumatology, The University of Hong Kong, Pokfulam, Hong Kong, SAR, China.
Juliana Tsz-Yan Lee
Department of Orthopaedics and Traumatology, The University of Hong Kong, Pokfulam, Hong Kong, SAR, China.
Cora H. Bow
Department of Orthopaedics and Traumatology, The University of Hong Kong, Pokfulam, Hong Kong, SAR, China.
Björn Meij
Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
Victor Leung
Department of Orthopaedics and Traumatology, The University of Hong Kong, Pokfulam, Hong Kong, SAR, China.
Kenneth M.C. Cheung
Department of Orthopaedics and Traumatology, The University of Hong Kong, Pokfulam, Hong Kong, SAR, China.
Patrick Vavken
Department of Orthopaedic Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
Harvard Center for Population and Development Studies, Harvard School of Public Health, Boston, Massachusetts.
Department of Orthopedic Surgery, University of Basel, Basel, Switzerland.
Dino Samartzis
Department of Orthopaedics and Traumatology, The University of Hong Kong, Pokfulam, Hong Kong, SAR, China.


Address correspondence to:Dino SamartzisDepartment of Orthopaedics and TraumatologyThe University of Hong KongProfessorial Block, 5th Floor102 Pokfulam RoadPokfulamHong Kong, SARChina
E-mail: [email protected]

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No competing financial interests exist.

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