Serious Adverse Events Have Not Been Reported with Spinal Intrathecal
Injection of Mesenchymal Stem Cells: A Systematic Review

Amir      Barmada; Joshua      Sharan; Nicolas      Band; Chadwick      Prodromos

doi:10.2174/1574888X17666220817125324

Abstract

Background: Mesenchymal stem cells (MSCs) are partially differentiated multipotent cells. They can be derived from various tissues such as the umbilical cord, bone marrow, and adipose tissue. Intrathecal administration of MSCs has shown efficacy for various neurological conditions including multiple sclerosis, autism, traumatic brain injury, and many more.

Objective: This review will seek to determine whether there are any serious adverse events associated with spinal intrathecal administration of MSCs.

Methods: PubMed was used to search the scientific literature for serious adverse events that are related to spinal intrathecal administration of MSCs. Disease specific searches were performed for neurological conditions that could benefit from intrathecal administration of MSCs. In addition, a general serious adverse events search was performed to identify any additional adverse events.

Results and Discussion: A total of 39 studies were included in our analysis. None of the studies reported serious adverse events related to spinal intrathecal administration of MSCs. Notably, no infections, clinical rejection, or tumors were identified.

Conclusion: Properly performed spinal intrathecal injection of MSCs is exceedingly safe, with no serious adverse events reported based on our exhaustive literature search.

Keywords: Mesenchymal stem cell, Stem cell, Safety, Review, Serious adverse events, Neurological diseases

« Previous Next »

Graphical Abstract

[1]
Ullah I, Subbarao RB, Rho GJ. Human mesenchymal stem cells - Current trends and future prospective. Biosci Rep  2015; 35(2): e00191.
 [http://dx.doi.org/10.1042/BSR20150025] [PMID:  25797907]

[2]
Lin W, Xu L, Zwingenberger S, Gibon E, Goodman SB, Li G. Mesenchymal stem cells homing to improve bone healing. J Orthop Translat  2017; 9: 19-27.
 [http://dx.doi.org/10.1016/j.jot.2017.03.002] [PMID:  29662796]

[3]
Fu X, Liu G, Halim A, Ju Y, Luo Q, Song AG. Mesenchymal stem cell migration and tissue repair. Cells  2019; 8(8): 784.
 [http://dx.doi.org/10.3390/cells8080784] [PMID:  31357692]

[4]
Murphy MB, Moncivais K, Caplan AI. Mesenchymal stem cells: Environmentally responsive therapeutics for regenerative medicine. Exp Mol Med  2013; 45(11): e54.
 [http://dx.doi.org/10.1038/emm.2013.94] [PMID:  24232253]

[5]
Ra JC, Shin IS, Kim SH, et al. Safety of intravenous infusion of human adipose tissue-derived mesenchymal stem cells in animals and humans. Stem Cells Dev  2011; 20(8): 1297-308.
 [http://dx.doi.org/10.1089/scd.2010.0466] [PMID:  21303266]

[6]
Wang L, Li Y, Xu M, et al. Regulation of inflammatory cytokine storms by mesenchymal stem cells. Front Immunol  2021; 12: 726909.
 [http://dx.doi.org/10.3389/fimmu.2021.726909] [PMID:  34394132]

[7]
Barczewska M, Maksymowicz S, Zdolińska-Malinowska I, Siwek T, Grudniak M. Umbilical cord mesenchymal stem cells in amyotrophic lateral sclerosis: An original study. Stem Cell Rev Rep  2020; 16(5): 922-32.
 [http://dx.doi.org/10.1007/s12015-020-10016-7] [PMID:  32725316]

[8]
Petrou P, Kassis I, Yaghmour NE, Ginzberg A, Karussis D. A phase II clinical trial with repeated intrathecal injections of autologous mesenchymal stem cells in patients with amyotrophic lateral sclerosis. Front Biosci  2021; 26(10): 693-706.
 [http://dx.doi.org/10.52586/4980] [PMID:  34719198]

[9]
Petrou P, Kassis I, Levin N, et al. Beneficial effects of autologous mesenchymal stem cell transplantation in active progressive multiple sclerosis. Brain  2020; 143(12): 3574-88.
 [http://dx.doi.org/10.1093/brain/awaa333] [PMID:  33253391]

[10]
Lv YT, Zhang Y, Liu M, et al. Transplantation of human cord blood mononuclear cells and umbilical cord-derived mesenchymal stem cells in autism. J Transl Med  2013; 11(1): 196.
 [http://dx.doi.org/10.1186/1479-5876-11-196] [PMID:  23978163]

[11]
Wang S, Cheng H, Dai G, et al. Umbilical cord mesenchymal stem cell transplantation significantly improves neurological function in patients with sequelae of traumatic brain injury. Brain Res  2013; 1532: 76-84.
 [http://dx.doi.org/10.1016/j.brainres.2013.08.001] [PMID:  23942181]

[12]
Alstadhaug KB, Odeh F, Baloch FK, Berg DH, Salvesen R. Post-lumbar puncture headache. Tidsskr Nor Laegeforen  2012; 132(7): 818-21.
 [http://dx.doi.org/10.4045/tidsskr.11.0832]

[13]
Cognat E, Koehl B, Lilamand M, et al. Preventing post-lumbar puncture headache. Ann Emerg Med  2021; 78(3): 443-50.
 [http://dx.doi.org/10.1016/j.annemergmed.2021.02.019] [PMID:  33966935]

[14]
Evans RW. Complications of lumbar puncture. Neurol Clin  1998; 16(1): 83-105.
 [http://dx.doi.org/10.1016/S0733-8619(05)70368-6] [PMID:  9421542]

[15]
Prodromos C, Rumschlag T. Administration of autologous mesenchymal cells for the treatment of arthritis. Curr Stem Cell Res Ther  2021; 16(8): 931-8.
 [http://dx.doi.org/10.2174/1574888X16666210224145104] [PMID:  33655846]

[16]
Connick P, Kolappan M, Crawley C, et al. Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: An open-label phase 2a proof-of-concept study. Lancet Neurol  2012; 11(2): 150-6.
 [http://dx.doi.org/10.1016/S1474-4422(11)70305-2] [PMID:  22236384]

[17]
Huang L, Zhang C, Gu J, et al. A randomized, placebo-controlled trial of human umbilical cord blood mesenchymal stem cell infusion for children with cerebral palsy. Cell Transplant  2018; 27(2): 325-34.
 [http://dx.doi.org/10.1177/0963689717729379] [PMID:  29637820]

[18]
Wang L, Wang L, Cong X, et al. Human umbilical cord mesenchymal stem cell therapy for patients with active rheumatoid arthritis: Safety and efficacy. Stem Cells Dev  2013; 22(24): 3192-202.
 [http://dx.doi.org/10.1089/scd.2013.0023] [PMID:  23941289]

[19]
Zhang J, Lv S, Liu X, Song B, Shi L. Umbilical cord mesenchymal stem cell treatment for Crohn’s Disease: A randomized controlled clinical trial. Gut Liver  2018; 12(1): 73-8.
 [http://dx.doi.org/10.5009/gnl17035] [PMID:  28873511]

[20]
Skyler JS, Fonseca VA, Segal KR, Rosenstock J. Allogeneic mesenchymal precursor cells in type 2 diabetes: A randomized, placebo-controlled, dose-escalation safety and tolerability pilot study. Diabetes Care  2015; 38(9): 1742-9.
 [http://dx.doi.org/10.2337/dc14-2830] [PMID:  26153271]

[21]
Llufriu S, Sepúlveda M, Blanco Y, et al. Randomized placebo-controlled phase II trial of autologous mesenchymal stem cells in multiple sclerosis. PLoS One  2014; 9(12): e113936.
 [http://dx.doi.org/10.1371/journal.pone.0113936] [PMID:  25436769]

[22]
Oh KW, Moon C, Kim HY, et al. Phase I trial of repeated intrathecal autologous bone marrow-derived mesenchymal stromal cells in amyotrophic lateral sclerosis. Stem Cells Transl Med  2015; 4(6): 590-7.
 [http://dx.doi.org/10.5966/sctm.2014-0212] [PMID:  25934946]

[23]
Karussis D, Karageorgiou C, Vaknin-Dembinsky A, et al. Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis. Arch Neurol  2010; 67(10): 1187-94.
 [http://dx.doi.org/10.1001/archneurol.2010.248] [PMID:  20937945]

[24]
Berry JD, Cudkowicz ME, Windebank AJ, et al. NurOwn, phase 2, randomized, clinical trial in patients with ALS: Safety, clinical, and biomarker results. Neurology  2019; 93(24): e2294-305.
 [http://dx.doi.org/10.1212/WNL.0000000000008620] [PMID:  31740545]

[25]
Mazzini L, Ferrero I, Luparello V, et al. Mesenchymal stem cell transplantation in amyotrophic lateral sclerosis: A Phase I clinical trial. Exp Neurol  2010; 223(1): 229-37.
 [http://dx.doi.org/10.1016/j.expneurol.2009.08.007] [PMID:  19682989]

[26]
Siwek T, Jezierska-Woźniak K, Maksymowicz S, et al. Repeat administration of bone marrow-derived mesenchymal stem cells for treatment of amyotrophic lateral sclerosis. Med Sci Monit  2020; 26: e927484.
 [http://dx.doi.org/10.12659/MSM.927484] [PMID:  33301428]

[27]
Rushkevich YN, Kosmacheva SM, Zabrodets GV, et al. The use of autologous mesenchymal stem cells for cell therapy of patients with amyotrophic lateral sclerosis in belarus. Bull Exp Biol Med  2015; 159(4): 576-81.
 [http://dx.doi.org/10.1007/s10517-015-3017-3] [PMID:  26395626]

[28]
Syková E, Rychmach P, Drahorádová I, et al. Transplantation of mesenchymal stromal cells in patients with amyotrophic lateral sclerosis: Results of phase I/IIa clinical trial. Cell Transplant  2017; 26(4): 647-58.
 [http://dx.doi.org/10.3727/096368916X693716] [PMID:  27938483]

[29]
Staff NP, Madigan NN, Morris J, et al. Safety of intrathecal autologous adipose-derived mesenchymal stromal cells in patients with ALS. Neurology  2016; 87(21): 2230-4.
 [http://dx.doi.org/10.1212/WNL.0000000000003359] [PMID:  27784774]

[30]
Oh KW, Noh MY, Kwon MS, et al. Repeated intrathecal mesenchymal stem cells for amyotrophic lateral sclerosis. Ann Neurol  2018; 84(3): 361-73.
 [http://dx.doi.org/10.1002/ana.25302] [PMID:  30048006]

[31]
Petrou P, Gothelf Y, Argov Z, et al. Safety and clinical effects of mesenchymal stem cells secreting neurotrophic factor transplantation in patients with amyotrophic lateral sclerosis: Results of phase 1/2 and 2a clinical trials. JAMA Neurol  2016; 73(3): 337-44.
 [http://dx.doi.org/10.1001/jamaneurol.2015.4321] [PMID:  26751635]

[32]
Bonab MM, Sahraian MA, Aghsaie A, et al. Autologous mesenchymal stem cell therapy in progressive multiple sclerosis: An open label study. Curr Stem Cell Res Ther  2012; 7(6): 407-14.
 [http://dx.doi.org/10.2174/157488812804484648] [PMID:  23061813]

[33]
Harris VK, Stark JW, Yang S, Zanker S, Tuddenham J, Sadiq SA. Mesenchymal stem cell-derived neural progenitors in progressive MS: Two-year follow-up of a phase I study. Neurol Neuroimmunol Neuroinflamm  2020; 8(1): e928.
 [http://dx.doi.org/10.1212/NXI.0000000000000928] [PMID:  33277427]

[34]
Dahbour S, Jamali F, Alhattab D, et al. Mesenchymal stem cells and conditioned media in the treatment of multiple sclerosis patients: Clinical, ophthalmological and radiological assessments of safety and efficacy. CNS Neurosci Ther  2017; 23(11): 866-74.
 [http://dx.doi.org/10.1111/cns.12759] [PMID:  28961381]

[35]
Harris VK, Stark J, Vyshkina T, et al. Phase I trial of intrathecal mesenchymal stem cell-derived neural progenitors in progressive multiple sclerosis. EBioMedicine  2018; 29: 23-30.
 [http://dx.doi.org/10.1016/j.ebiom.2018.02.002] [PMID:  29449193]

[36]
Sharifzadeh N, Ghasemi A, Tavakol Afshari J, et al. Intrathecal autologous bone marrow stem cell therapy in children with autism: A randomized controlled trial. Asia-Pac Psychiatry  2021; 13(2): e12445.
 [http://dx.doi.org/10.1111/appy.12445] [PMID:  33150703]

[37]
Tian C, Wang X, Wang X, et al. Autologous bone marrow mesenchymal stem cell therapy in the subacute stage of traumatic brain injury by lumbar puncture. Exp Clin Transplant  2013; 11(2): 176-81.
 [http://dx.doi.org/10.6002/ect.2012.0053] [PMID:  22891928]

[38]
Wang Z, Luo Y, Chen L, Liang W. Safety of neural stem cell transplantation in patients with severe traumatic brain injury. Exp Ther Med  2017; 13(6): 3613-8.
 [http://dx.doi.org/10.3892/etm.2017.4423] [PMID:  28588689]

[39]
Chen G, Wang Y, Xu Z, et al. Neural stem cell-like cells derived from autologous bone mesenchymal stem cells for the treatment of patients with cerebral palsy. J Transl Med  2013; 11(1): 21.
 [http://dx.doi.org/10.1186/1479-5876-11-21] [PMID:  23351389]

[40]
Liu X, Fu X, Dai G, et al. Comparative analysis of curative effect of bone marrow mesenchymal stem cell and bone marrow mononuclear cell transplantation for spastic cerebral palsy. J Transl Med  2017; 15(1): 48.
 [http://dx.doi.org/10.1186/s12967-017-1149-0] [PMID:  28235424]

[41]
Amanat M, Majmaa A, Zarrabi M, et al. Clinical and imaging outcomes after intrathecal injection of umbilical cord tissue mesenchymal stem cells in cerebral palsy: A randomized double-blind sham-controlled clinical trial. Stem Cell Res Ther  2021; 12(1): 439.
 [http://dx.doi.org/10.1186/s13287-021-02513-4] [PMID:  34362453]

[42]
Wang X, Cheng H, Hua R, et al. Effects of bone marrow mesenchymal stromal cells on gross motor function measure scores of children with cerebral palsy: A preliminary clinical study. Cytotherapy  2013; 15(12): 1549-62.
 [http://dx.doi.org/10.1016/j.jcyt.2013.06.001] [PMID:  24100132]

[43]
Wang X, Hu H, Hua R, et al. Effect of umbilical cord mesenchymal stromal cells on motor functions of identical twins with cerebral palsy: Pilot study on the correlation of efficacy and hereditary factors. Cytotherapy  2015; 17(2): 224-31.
 [http://dx.doi.org/10.1016/j.jcyt.2014.09.010] [PMID:  25593078]

[44]
Ahn SY, Chang YS, Kim JH, Sung SI, Park WS. Two-year follow-up outcomes of premature infants enrolled in the phase I trial of mesenchymal stem cells transplantation for bronchopulmonary dysplasia. J Pediatr  2017; 185: 49-54.e2.
 [http://dx.doi.org/10.1016/j.jpeds.2017.02.061] [PMID:  28341525]

[45]
Yang Y, Pang M, Du C, et al. Repeated subarachnoid administrations of allogeneic human umbilical cord mesenchymal stem cells for spinal cord injury: A phase 1/2 pilot study. Cytotherapy  2021; 23(1): 57-64.
 [http://dx.doi.org/10.1016/j.jcyt.2020.09.012] [PMID:  33218835]

[46]
Satti HS, Waheed A, Ahmed P, et al. Autologous mesenchymal stromal cell transplantation for spinal cord injury: A Phase I pilot study. Cytotherapy  2016; 18(4): 518-22.
 [http://dx.doi.org/10.1016/j.jcyt.2016.01.004] [PMID:  26971680]

[47]
Albu S, Kumru H, Coll R, et al. Clinical effects of intrathecal administration of expanded Wharton jelly mesenchymal stromal cells in patients with chronic complete spinal cord injury: A randomized controlled study. Cytotherapy  2021; 23(2): 146-56.
 [http://dx.doi.org/10.1016/j.jcyt.2020.08.008] [PMID:  32981857]

[48]
Cheng H, Liu X, Hua R, et al. Clinical observation of umbilical cord mesenchymal stem cell transplantation in treatment for sequelae of thoracolumbar spinal cord injury. J Transl Med  2014; 12(1): 253.
 [http://dx.doi.org/10.1186/s12967-014-0253-7] [PMID:  25209445]

[49]
Vaquero J, Zurita M, Rico MA, et al. Intrathecal administration of autologous mesenchymal stromal cells for spinal cord injury: Safety and efficacy of the 100/3 guideline. Cytotherapy  2018; 20(6): 806-19.
 [http://dx.doi.org/10.1016/j.jcyt.2018.03.032] [PMID:  29853256]

[50]
Karamouzian S, Nematollahi-Mahani SN, Nakhaee N, Eskandary H. Clinical safety and primary efficacy of bone marrow mesenchymal cell transplantation in subacute spinal cord injured patients. Clin Neurol Neurosurg  2012; 114(7): 935-9.
 [http://dx.doi.org/10.1016/j.clineuro.2012.02.003] [PMID:  22464434]

[51]
Vaquero J, Zurita M, Rico MA, et al. Repeated subarachnoid administrations of autologous mesenchymal stromal cells supported in autologous plasma improve quality of life in patients suffering incomplete spinal cord injury. Cytotherapy  2017; 19(3): 349-59.
 [http://dx.doi.org/10.1016/j.jcyt.2016.12.002] [PMID:  28089079]

[52]
Hur JW, Cho TH, Park DH, Lee JB, Park JY, Chung YG. Intrathecal transplantation of autologous adipose-derived mesenchymal stem cells for treating spinal cord injury: A human trial. J Spinal Cord Med  2016; 39(6): 655-64.
 [http://dx.doi.org/10.1179/2045772315Y.0000000048] [PMID:  26208177]

[53]
Pal R, Venkataramana NK, Bansal A, et al. Ex vivo-expanded autologous bone marrow-derived mesenchymal stromal cells in human spinal cord injury/paraplegia: A pilot clinical study. Cytotherapy  2009; 11(7): 897-911.
 [http://dx.doi.org/10.3109/14653240903253857] [PMID:  19903102]

[54]
Singer W, Dietz AB, Zeller AD, et al. Intrathecal administration of autologous mesenchymal stem cells in multiple system atrophy. Neurology  2019; 93(1): e77-87.
 [http://dx.doi.org/10.1212/WNL.0000000000007720] [PMID:  31152011]

[55]
Jin JL, Liu Z, Lu ZJ, et al. Safety and efficacy of umbilical cord mesenchymal stem cell therapy in hereditary spinocerebellar ataxia. Curr Neurovasc Res  2013; 10(1): 11-20.
 [http://dx.doi.org/10.2174/156720213804805936] [PMID:  23151076]

[56]
Feldmesser M. Fungal disease following contaminated steroid injections: Exserohilum is ready for its close-up. Am J Pathol  2013; 183(3): 661-4.
 [http://dx.doi.org/10.1016/j.ajpath.2013.06.010] [PMID:  23876717]

[57]
Kauffman CA, Malani AN. Fungal infections associated with contaminated steroid injections. Microbiol Spectr  2016; 4(2): 4.2.23.
 [http://dx.doi.org/10.1128/microbiolspec.EI10-0005-2015] [PMID: 27227303]

Rights & Permissions Print Cite

Article Metrics

3

Journal Information

For Authors

For Editors

For Reviewers

Explore Articles

Open Access

Open Access Articles

For Visitors

DOI https://dx.doi.org/10.2174/1574888X17666220817125324	Print ISSN 1574-888X
Publisher Name Bentham Science Publisher	Online ISSN 2212-3946

Current Stem Cell Research & Therapy

Serious Adverse Events Have Not Been Reported with Spinal Intrathecal Injection of Mesenchymal Stem Cells: A Systematic Review

Abstract Play Pause

Graphical Abstract

Related Books

Abstract