Outcome of Stem Cell Transplantation in Patient with Spinal Cord Injury: A Systematic Review

Spinal cord injury (SCI) is well known as a severely disabling injury that can result in long term neurological impairment and a great impact on social and economic aspects of the patients. To investigate the controversy regarding Stem Cell Transplantation as a treatment modality to alleviate the devastating effect of Spinal Cord Injury, we performed literature research according to PRISMA guidelines through Pubmed, Cochrane, and EMBASE Library to find studies about SCI and its stem cell management up to October 20 th , 2020 with the keywords "stem cell transplantation" OR "spinal mesenchymal stem cell" OR "treatment" AND "spinal cord injury" OR "traumatic spinal cord injury") OR "outcome “ . The search was filtered to include clinical human studies in last 5 years publication period and written in English only. A total of 15 non-duplicate citations were found. 14 articles remained after a title and abstract screening. Ten studies are excluded from this study because they do not contain any outcomes of interest. Four articles are selected for this systematic review. A total of 72 patients were included in this review from 4 prospective cohort studies. Most studies classified their neurological status based on ASIA (American Spinal Injury Association) classification for quantifying the SCI severity. In conclusion, Stem Cell transplantation yielded satisfactory results in comparison to conventional management of SCI patients. Future studies with longer terms should be performed to cement the validity of this finding.

neural apoptosis of the spinal cord (Kakulas et al., 2015). Besides that, another condition such as oxidative stress and disturbance of electrolyte also can lead to SCI. Some other condition can cause both primary, and also secondary SCI such as demyelination, severe tissue destruction, Wallerian degeneration, axonotmesis, syringomyelia, and formation of glial scar. There were some approach and strategies that have been developed and proposed to this condition, including surgery techniques, medications, and rehabilitation. But, there were still questions regarding the efficacy of the treatment options (Xu et al., 2019).
Recently, the standard of care for acute SCI is surgical treatments which mainly aim to spinal cord decompression and rehabilitation (Sunshine et al., 2017). However, there is still no neuroprotective and regenerative modalities that is effective and useful. Highdose methylprednisolone has been proposed to have beneficial effects in patients with SCI, but the consensus on the efficacy of this approach is still unclear (Qin et al., 2018). The clinical use of stem cell transplantation has become new trend in these decade and some studies reported its effectiveness in treating SCI in animal models. Some variety of stem cells which consist of neural stem cells, mesenchymal stem cells (MSCs), Schwann cells, embryonic stem cells, and induced pluripotent stem cells have been used and developed for transplantation. Among these stem cell variety, MSCs have been known for its importance in repairing the damaged spinal cord (Muheremu et al., 2016). Beside their superiority in differentiation and replacement for the damaged cells, MSCs also secrete many neuroprotective factors and cytokines, including brain-derived neurotrophic factor (BDNF), glial-cell-line-derived neurotrophic factor (GDNF) and vascular endothelial growth factor (VE-GF). The fore mentioned factors had important roles in improving regeneration of neural tissues, promoting axon growth, and repairing damaged neurons. Currently, the outcome of MSCs transplantation to treat SCI in animal models have been verified (Abbasi et al., 2021;Cho et al., 2009) .
Despite of its effect on animal models, the outcome of MSCs in treating SCI in humans is still questionable. No review study has extensively evaluated the outcome of MSCs for SCI treatment. These studies will discuss previous studies investigating the outcome of stem cell transplantation usage in treating patient with SCI.

Review of Literature
Search strategy This systematic review was arranged based on the PRISMA guideline (Fig. 1). Full-text articles assessed for eligibility (n = 14) Full-text articles excluded, with reasons (n = 10) Studies included in qualitative synthesis (n = 4)

Inclusion criteria
The inclusion criteria were outcome of stem cell transplantation for the management of SCI. Case series and case reports were also included in this review. Due to the limited number of studies, we did not establish restriction for demographics of the patients, though some reports and literatures not in English were excluded. Study that focus in rat study of stem cell transplantation and systemic review study are excluded from this review ( Table 1).

Quality evaluation
After the search was performed, all authors screened to find studies which eligible. The all authors read the titles and abstracts and choose the article according to the inclusion criteria. Then, all authors continued to screen the full version of articles collected. The authors then gathered together and discussed about highly relevant studies that would be included in this review. Appraisal of study quality was performed by each authors independently and discussion was held if there was any disagreement about the selection and appraisal of the studies. The inherent aspects of the studies that consist of quality of the study, variables of relevant data, and also bias risk assessment were independently appraised by all authors by using forms filled by themselves. The first author then collected the forms and the contents of the form were evaluated to find any possible disagreements. The authors then had a meeting again to talk about any contradictions found and to find the decision according the appraisal of the studies.

Study Selection
A total of 15 non-duplicate citations were found. 14 articles remained after a title and abstract screen. Full texts were screened using the pre-determined exclusion and inclusion criteria. Ten studies has to be excluded from the review because they do not have any out-comes of interest. Four articles were selected for this systematic review.

Study Characteristics
There were 72 patients in total were included in this review. 62 patients underwent operative management while 10 patients had non-operative management.    The all of them were only mild and temporary side effects, including fever, headache, urinary tract infections, nausea, numbness, backache, and abdominal distension, which mainly due to spinal puncture. There were no puncture wound infection, intracranial in-fection, leakage of cerebrospinal fluid from the incision, or any other severe or long term adverse effects observed in the subjects, indicating that stem cell transplantation is a considerably safe modality. There were some limitations exist in this study. First, this review only included 4 studies due to the limitation of literatures, so there were some important subgroup analyses that was not be able to be performed such as the disease's different courses and number of cells transplanted to the subjects. The second limitation is that only papers published in English were included in this systematic review, so there may be another eligible studies in language other than English that relevant and can be included in this review. Review which included multi-centric randomized control trials with large size of randomizes subjects, reasonable generation of random sequence, adequate allocation concealment, and low risk of reporting bias will be needed to find evidence base with higher quality.

CONCLUSION:
Stem cells transplantation yielded satisfactory result in comparison to conventional management of SCI pati-ents, in which all the patients was found to have improvement after stem cells administration based on ASIA assessment. Many neuroprotective factors and cytokines, including BDNF, GDNF, and VEGF that were secreted by MSCs thought to be the reason in its superiority in differentiation and replacement for the damaged cells. Some adverse effects were observed, including fever, headache, urinary tract infections, nausea, numbness, backache, and abdominal distension, which mainly due to spinal puncture, and were found to be only mild and temporary. There was no puncture wound infection, leakage of cerebrospinal fluid from the incision, intracranial infection, or any other severe or long term adverse effects observed in the subjects, indicating that stem cell transplantation is a considerably safe modality. Future prospective studies with longer observation periods should be performed to cement the validity of this finding.