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Is cell transplantation a reliable therapeutic strategy for spinal cord injury in clinical practice? A systematic review and meta-analysis from 22 clinical controlled trials

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A Correction to this article was published on 23 June 2020

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Abstract

Purpose

It is an open question whether cell transplantation can provide safety and effective outcome to spinal cord injury (SCI) patient which has remained controversial for almost 40 years. This study aimed to evaluate the safety and efficacy of cell transplantation in SCI patients.

Method

Studies of the cell transplantation for SCI were retrieved from PubMed, Embase, Medline, Cochrane Library and analyzed quantitative data by Review Manager 5.3.

Results

Twenty-one clinical controlled studies with 973 patients were included. The pooled results suggested that cell transplantation significantly improved ASIA score, ASIA motor score, ASIA sensory score, Barthel Index score, residual urine volume, rehabilitative time of automatic micturition. Furthermore, subgroup analysis indicated that the stem cells exhibited more potent than the non-stem cells in spinal cord repair. Cell transplantation at more than 14 days after injury showed more significant improvements than that within 14 days from injury. The dosage of cell transplantation between 1–5 × 107 and 10–20 × 107 was the potent quantity for the patient with SCI. Intrathecal injection and intravenous + intrathecal injection showed more superior to the other method. The top 5 adverse events were febrile reaction (11.5%), neurologic pain (11.3%), headache (2.6%), neurologic deterioration (2.4%), and rigidity or spasticity (1.6%).

Conclusion

Cell transplantation appears to be a safe therapeutic strategy possessing substantial beneficial effects in the patients with SCI in clinic. Moreover, treating SCI with stem cell, the dosage of cells between 1–5 × 107 and 10–20 × 107, in intermediate or chronic phase, minimally invasive techniques, may bring more advantage to SCI patient.

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Change history

  • 23 June 2020

    Zhao-he and Sun-qingling are the co-first authors for this manuscript in the initial submission. Because of author���s negligence and fault, this information was not shown clearly in the originally published article.

Abbreviations

ADSCs:

Adipose-derived stem cells

BMSCs:

Bone mesenchymal stem cell

MMCs:

Marrow mononuclear cells

UCMSCs:

Umbilical cord-derived mesenchymal stem cells

OECs:

Olfactory ensheathing cells

AIM:

Autologous incubated macrophage

SCs:

Schwann cells

OLP:

Olfactory lamina propria

GM-CSF:

Granulocyte-macrophage colony-stimulating factor

FB-DNS/PCs:

Fetal brain-derived neural stem/progenitor cell

CNS:

Central nervous system

References

  1. Silva NA, Sousa N, Reis RL (2014) From basics to clinical: a comprehensive review on spinal cord injury. Prog Neurobiol 114:25–57

    PubMed  Google Scholar 

  2. Devivo MJ (2012) Epidemiology of traumatic spinal cord injury: trends and future implications. Spinal Cord 50:365–372

    CAS  PubMed  Google Scholar 

  3. Lee BB, Cripps RA, Fitzharris M et al (2011) The global map for traumatic spinal cord injury epidemiology: update, global incidence rate. Spinal Cord 52(2):110–116

    Google Scholar 

  4. Hurlbert RJ, Hadley MN, Walters BC et al (2015) Pharmacological therapy for acute spinal cord injury. Neurosurgery 76:S71–S83

    PubMed  Google Scholar 

  5. Miller SM (2008) Methylprednisolone in acute spinal cord injury: a tarnished standard. J Neurosurg Anesthesiol 20(2):140–142

    PubMed  Google Scholar 

  6. Breslin K, Agrawal D (2012) The use of methylprednisolone in acute spinal cord injury: a review of the evidence, controversies, and recommendations. Pediatr Emerg Care 28(11):1238–1245

    PubMed  Google Scholar 

  7. Ahuja CS, Nori S, Tetreault L et al (2017) Traumatic spinal cord injury-repair and regeneration. Neurosurgery 80(3S):S9–S22

    PubMed  Google Scholar 

  8. Grossman RG, Fehlings MG, Frankowski RF et al (2014) A prospective, multicenter, phase I matched-comparison group trial of safety, pharmacokinetics, and preliminary efficacy of riluzole in patients with traumatic spinal cord injury. J Neurotrauma 31(3):239–255

    PubMed  PubMed Central  Google Scholar 

  9. Streijger F, Lee JH, Manouchehri N et al (2016) The evaluation of magnesium chloride within a polyethylene glycol formulation in a porcine model of acute spinal cord injury. J Neurotrauma 33(24):2202–2216

    PubMed  Google Scholar 

  10. Sledge J, Mahadevappa K, Stacey P et al (2016) A speculative pharmaceutical cocktail to treat spinal cord injury. Am J Phys Med Rehabil 95(7):e108–e110

    PubMed  Google Scholar 

  11. Thuret S, Moon LD, Gage FH (2006) Therapeutic interventions after spinal cord injury. Nat Rev Neurosci 7(8):628–643

    CAS  PubMed  Google Scholar 

  12. Raspa A, Pugliese R, Maleki M et al (2016) Recent therapeutic approaches for spinal cord injury. Biotechnol Bioeng 113(2):253–259

    CAS  PubMed  Google Scholar 

  13. Marino G, Rosso F, Ferdinando P et al (2012) Growth and endothelial differentiation of adipose stem cells on polycaprolactone. J Biomed Mater Res A 100(3):543–548

    PubMed  Google Scholar 

  14. Barbarisi M, Marino G, Armenia E (2015) Use of polycaprolactone (PCL) as scaffolds for the regeneration of nerve tissue. J Biomed Mater Res A 103(5):1755–1760

    PubMed  Google Scholar 

  15. Sahni V, Kessler JA (2010) Stem cell therapies for spinal cord injury. Nat Rev Neurol 6(7):363–372

    PubMed  PubMed Central  Google Scholar 

  16. Ruff CA, Wilcox JT, Fehlings MG (2012) Cell-based transplantation strategies to promote plasticity following spinal cord injury. Exp Neurol 235(1):78–90

    PubMed  Google Scholar 

  17. Li XC, Zhong CF, Deng GB et al (2015) Efficacy and safety of bone marrow-derived cell transplantation for spinal cord injury: a systematic review and meta-analysis of clinical trials. Clin Transpl 29(9):786–795

    Google Scholar 

  18. Li L, Adnan H, Xu B (2015) Effects of transplantation of olfactory ensheathing cells in chronic spinal cord injury: a systematic review and meta-analysis. Eur Spine J 24(5):919–930

    PubMed  Google Scholar 

  19. Fan X, Wang JZ, Lin XM et al (2017) Stem cell transplantation for spinal cord injury: a meta-analysis of treatment effectiveness and safety. Neural Regen Res 12(5):815–825

    PubMed  PubMed Central  Google Scholar 

  20. Liu J, Chen P, Wang Q et al (2014) Meta analysis of olfactory ensheathing cell transplantation promoting functional recovery of motor nerves in rats with complete spinal cord transection. Neural Regen Res 9(20):1850–1858

    PubMed  PubMed Central  Google Scholar 

  21. Oliveri RS, Bello S, Biering-Sørensen F (2014) Mesenchymal stem cells improve locomotor recovery in traumatic spinal cord injury: systematic review with meta-analyses of rat models. Neurobiol Dis 62:338–353

    CAS  PubMed  Google Scholar 

  22. Kim JH, Shim SR, Doo SW et al (2015) Bladder recovery by stem cell based cell therapy in the bladder dysfunction induced by spinal cord injury: systematic review and meta-analysis. PLoS ONE 10(3):e0113491

    PubMed  PubMed Central  Google Scholar 

  23. Yang L, Ge Y, Tang J (2015) Schwann cells transplantation improves locomotor recovery in rat models with spinal cord injury: a systematic review and meta-analysis. Cell Physiol Biochem 37(6):2171–2182

    CAS  PubMed  Google Scholar 

  24. Yousefifard M, Rahimi-Movaghar V, Nasirinezhad F et al (2016) Neural stem/progenitor cell transplantation for spinal cord injury treatment; A systematic review and meta-analysis. Neuroscience 322:377–397

    CAS  PubMed  Google Scholar 

  25. Chen X, Xue B, Li Y et al (2017) Meta-analysis of stem cell transplantation for reflex hypersensitivity after spinal cord injury. Neuroscience 363:66–75

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Watzlawick R, Rind J, Sena ES et al (2016) Olfactory ensheathing cell transplantation in experimental spinal cord injury: effect size and reporting bias of 62 experimental treatments: a systematic review and meta-analysis. PLoS Biol 14(5):e1002468

    PubMed  PubMed Central  Google Scholar 

  27. Antonic A, Sena ES, Lees JS et al (2013) Stem cell transplantation in traumatic spinal cord injury: a systematic review and meta-analysis of animal studies. PLoS Biol 11(12):e1001738

    PubMed  PubMed Central  Google Scholar 

  28. Chernykh ER, Stupak VV, Muradov GM et al (2007) Application of autologous bone marrow stem cells in the therapy of spinal cord injury patients. Bull Exp Biol Med 143(4):543–547

    CAS  PubMed  Google Scholar 

  29. Yoon SH, Shim YS, Park YH et al (2007) Complete spinal cord injury treatment using autologous bone marrow cell transplantation and bone marrow stimulation with granulocyte macrophage-colony stimulating factor: phase I/II clinical trial. Stem Cells 25(8):2066–2073

    PubMed  Google Scholar 

  30. Xie ZW, Cui GX, Li YZ et al (2007) Curative effect of autologous mesenchymal stem cell transplantation on spinal cord injury. J Clin Rehabil Tissue Eng Res 11(5):1277–1279

    Google Scholar 

  31. Cui GX, Song CZ, Li YZ et al (2009) Clinical study of autologous marrow mononuclear cells transplantation in patients with spinal cord injury. Chin J Rehabil Med 24(13):309–312

    Google Scholar 

  32. Nirmeen A, Gabr H, Hamdy S et al (2010) Case control series of intrathecal autologous bone marrow mesenchymal stem cell therapy for chronic spinal cord injury. Neurorehabil Neural Re 24(8):702–708

    Google Scholar 

  33. Fang ML, Wang MX, Wang YQ et al (2011) Clinical study of autologous mesenchymal stem cell transplantation on spinal cord injury. J Qiqihar Univ Med 32(4):2064–2066

    Google Scholar 

  34. Karamouzian S, Nematollahi-Mahani SN, Nakhaee N et al (2012) Clinical safety and primary efficacy of bone marrow mesenchymal cell transplantation in subacute spinal cord injured patients. Clin Neurol Neurosurg 114(7):935–939

    PubMed  Google Scholar 

  35. Xiao YL, Zhu JX, Li ZM et al (2012) The therapeutic effects of two different ways of autalogous bone marrow mesenchymal stem cells transplantation for treating early spinal cord injury. Chin J Postgrad Med 35(9):24–28

    Google Scholar 

  36. Guo GH, Shen LF, Li Z (2012) Clinical studies of umbilical cord blood mesenchymal stem cells transplantation on spinal cord injury. Chin J Pract Med 39(9):58–60

    Google Scholar 

  37. Zhang XB, Li JT, Zhao HT et al (2012) Umbilical cord blood mesenchymal stem cells transplantation on spinal cord injury in clinical study. Asia Pac Tradit Med 8:116–117

    CAS  Google Scholar 

  38. Lammertse DP, Jones LA, Charlifue SB et al (2012) Autologous incubated macrophage therapy in acute, complete spinal cord injury: results of the phase 2 randomized controlled multicenter trial. Spinal Cord 50(9):661–671

    CAS  PubMed  Google Scholar 

  39. Dai GH, Liu X, Zhang Z et al (2013) Transplantation of autologous bone marrow mesenchymal stem cells in the treatment of complete and chronic cervical spinal cord injury. Brain Res 1533:73–79

    CAS  PubMed  Google Scholar 

  40. Tabakow P, Jarmundowicz W, Czapiga B et al (2013) Transplantation of autologous olfactory ensheathing cells in complete human spinal cord injury. Cell Transpl 22(9):1591–1612

    Google Scholar 

  41. Guo ZS, Qin BY, Dai RX et al (2014) Bone marrow mesenchymal stem cells in the treatment of spinal cord injury. Chin J Exp Surg 32(7):2605–2607

    Google Scholar 

  42. Xiao YL, Li ZM, Zhu JX et al (2014) Efficacy observation of autologous bone marrow-derived mesenchymal stem cell therapy on early spinal cord injury. Chin J Biomed Eng 20(1):7–11

    Google Scholar 

  43. Cheng HB, Liu X, Hua R et al (2014) Clinical observation of umbilical cord mesenchymal stem cell transplantation in treatment for sequelae of thoracolumbar spinal cord injury. J Transl Med 12:253

    PubMed  PubMed Central  Google Scholar 

  44. El-Kheir WA, Gabr H, Awad MR et al (2014) Autologous bone marrow-derived cell therapy combined with physical therapy induces functional improvement in chronic spinal cord injury patients. Cell Transpl 23(6):729–745

    Google Scholar 

  45. Chen L, Huang H, Xi H et al (2014) A prospective randomized double-blind clinical trial using a combination of olfactory ensheathing cells and Schwann cells for the treatment of chronic complete spinal cord injuries. Cell Transpl 23(1):S35–S44

    Google Scholar 

  46. Shin JC, Kim KN, Yoo J et al (2015) Clinical trial of human fetal brain-derived neural stem/progenitor cell transplantation in patients with traumatic cervical spinal cord injury. Neural Plast 2015:630932

    PubMed  PubMed Central  Google Scholar 

  47. Zhang Z, Dai GH, Liu XB et al (2015) Umbilical cord mesenchymal stem cell transplantation for spinal cord injury. J Chin Pract Diagn Ther 29(3):478–480

    Google Scholar 

  48. Zhang T, Tong X, Liu C (2015) Efficacy observation of autologous bone marrow-derived mesenchymal stem cell therapy on chronic spinal cord injury. Word New Inf 15:65–66

    Google Scholar 

  49. Wang S, Lu J, Li YA et al (2016) Autologous olfactory lamina propria transplantation for chronic spinal cord injury: three-year follow-up outcomes from a prospective double-blinded clinical trial. Cell Transpl 25(1):141–157

    Google Scholar 

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Acknowledgments

Thank you so much for contributions made by all members of Pro. Xiu-Mei Wang`s group (School of Materials Science and Engineering, Tsinghua University). Thank you so much for contributions made by all members in department of orthopedics III (Dongzhimen Hospital, Beijing University of Chinese Medicine). Thank you so much for contributions made by Dr. Feng-He (China Academy of Chinese Medical Science), Dr. Wan-Jie Gu (Drum Tower, Medical College of Nanjing University), Dr. Yun-Tao Zhao(Aerospace Center Hospital, Peking University).

Funding

This work was funded by the National Twelfth Five-Year Plan for Science and Technology Support (Grant No. 2012BAI18B05).

Author information

Authors and Affiliations

  1. School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, China

    He Zhao & Xiu-Mei Wang

  2. Department of Geriatric, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China

    Qing-Ling Sun

  3. Department of Orthopedics III, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China

    He Zhao, Li-Jun Duan, Yong-Dong Yang, Ding-Yan Zhao, Yang Xiong, He-Jun Wang, Jia-Wei Song, Kai-Tan Yang & Xing Yu

  4. Department of Basic Medical Sciences, Beijing University of Chinese Medicine, Beijing, 100029, China

    Yu-Shan Gao

  5. Department of Orthopedics, Bayannaoer City Hospital, Bayannaoer City, 015000, Inner Mongolia, China

    Li-Jun Duan

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  1. He Zhao
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Contributions

HZ, XMW, and XY designed the systematic review. HZ and QLS drafted the protocol, and LJD, YDY, YSG, and DYZ revised the manuscript. YX and HJW will independently screen the potential studies, extract data, assess the risk of bias, and finish data synthesis. JWS and KTY will arbitrate any disagreements during the review. All authors approved the publication of the manuscript.

Corresponding authors

Correspondence to Xiu-Mei Wang or Xing Yu.

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Conflict of interest

Authors declare that they have no conflict of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplement 1

ASIA subgroup stem cell VS. non-stem cell (TIFF 1367 kb)

Supplement 2

ASIA subgroup phase (TIFF 1520 kb)

Supplement 3

ASIA subgroup cell number (TIFF 1630 kb)

Supplement 4

ASIA motion subgroup stem cell VS. non-stem cell (TIFF 1488 kb)

Supplement 5

ASIA motion subgroup phase (TIFF 1618 kb)

Supplement 6

ASIA motion subgroup cell number (TIFF 1723 kb)

Supplement 7

ASIA sensation subgroup stem cell VS. non-stem cell (TIFF 1497 kb)

Supplement 8

ASIA sensation subgroup phase (TIFF 1635 kb)

Supplement 9

ASIA sensation subgroup cell number (TIFF 1742 kb)

Supplement 10

ASIA subgroup cell transplantation techniques (TIFF 1632 kb)

Supplement 11

ASIA motion subgroup cell transplantation techniques (TIFF 2174 kb)

Supplement 12

ASIA sensation subgroup cell transplantation techniques (TIFF 2215 kb)

Supplement 13

Sensitive analysis of cell transplantation techniques in ASIA score (TIFF 1176 kb)

Supplement 14

Sensitive analysis of cell transplantation techniques in ASIA motion (TIFF 1250 kb)

Supplement 15

Sensitive analysis of cell transplantation techniques in ASIA sensation (TIFF 1263 kb)

Supplement 16

Barthal Index subgroup stem cell VS. non-stem cell (TIFF 853 kb)

Supplement 17

Barthal Index subgroup phase (TIFF 855 kb)

Supplement 18

Barthal Index subgroup cell number (TIFF 1211 kb)

Supplement 19

Residental urinal subgroup stem cell VS. non-stem cell (TIFF 615 kb)

Supplement 20

Rehabilitative time of automatic micturition subgroup stem cell VS. non-stem cell (TIFF 678 kb)

Supplementary material 21 (PPTX 1176 kb)

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Zhao, H., Sun, QL., Duan, LJ. et al. Is cell transplantation a reliable therapeutic strategy for spinal cord injury in clinical practice? A systematic review and meta-analysis from 22 clinical controlled trials. Eur Spine J 28, 1092–1112 (2019). https://doi.org/10.1007/s00586-019-05882-w

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  • DOI: https://doi.org/10.1007/s00586-019-05882-w

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