Transplantation of rat cranial bone-derived mesenchymal stem cells promotes functional recovery in rats with spinal cord injury

Maeda, Yuyo; Otsuka, Takashi; Takeda, Masaaki; Okazaki, Taro; Shimizu, Kiyoharu; Kuwabara, Masashi; Hosogai, Masahiro; Yuge, Louis; Mitsuhara, Takafumi

doi:10.1038/s41598-021-01490-1

Cited by 17 publications

(26 citation statements)

References 53 publications

(69 reference statements)

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“…This spurs numerous efforts to isolate and characterize MSCs from a variety of human tissues for their potential clinical applications (Pikuła et al, 2013 ; Miura, 2016 ; Van Pham et al, 2016 ; Yamada et al, 2019 ). Previous studies in our lab and others have demonstrated the neurogenic potential of CB-MSCs and their contributions to ameliorating neural injury in rat models (Abiko et al, 2018 ; Ma et al, 2019 ; Maeda et al, 2021 ). The overall goal of this study was to further investigate isolated CB-MSCs at clonal level with specific emphasis on the transdifferentiation capacity and immunoregulatory functions, which are two key features that need to be elucidated as required to move forward for the development of MSCs-based therapies.…”

Section: Discussionmentioning

confidence: 83%

“…Among all tissues, cranial bone marrow have attracted interest as a promising source of MSCs with remarkable neurogenic potential. It has been reported that intravenous transplantation of MSCs isolated from cranial bone marrow (CB-MSCs) promoted functional recovery and improved motor function in rats after ischemic stroke and spinal cord injury, respectively (Abiko et al, 2018 ; Maeda et al, 2021 ). In line with these observations, previous studies in our lab demonstrated that human CB-MSCs were highly inducible into neuron-like cells with robust expression of neural markers (Ma et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

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Phenotypic and Functional Characterizations of Mesenchymal Stem/Stromal Cells Isolated From Human Cranial Bone Marrow

Yang

Lu²,

Lu³

et al. 2022

Front. Neurosci.

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Mesenchymal stem/stromal cells (MSCs) are adult stem cells that were originally isolated from bone marrow. In contrast to long bone-derived MSCs that have been extensively characterized, our knowledge regarding to MSCs isolated from flat bones (e.g., cranial bones) remain less clear. In this study, MSCs were purified from human cranial bone marrow (CB-MSCs) and their transdifferentiation capacity and immunomodulatory functions were further characterized. Phenotypic analysis of CB-MSCs demonstrated high expression of CD73, CD90, and CD105 while negative for CD14, CD34, and HLA-DR. Further in vitro differentiation assay shown that CB-MSCs capable of differentiating into cell types of mesenchymal origin (i.e., adipocytes, osetoblasts, and chondrocytes) and collectively, these results indicated that cells isolated from cranial bone marrow in this study are bona fide MSCs according to the minimal criteria proposed by the International Society for Cellular Therapy. Following in vitro expansion, single colony-derived CB-MSCs (scCB-MSCs) were obtained and confocal microscopy analysis further revealed functional heterogeneity within primary CB-MSCs. Specifically, obtained scCB-MSCs exhibited GABA progenitor features, as determined by olig2 and nestin. As expect, scCB-MSCs were readily induced to differentiate into GABAergic neuron-like cells. Furthermore, immunomodulatory roles of scCB-MSCs were evaluated following co-culture with human peripheral blood lymphocytes and results shown that co-culturing with scCB-MSCs significantly suppressed lymphocyte proliferation and promoted differentiation of lymphocytes into regulatory T cells but not Th1/Th17 phenotype. Overall, our results indicated that CB-MSCs exhibited clonal heterogeneity with marked propensity to differentiate into neural-like cells and this might represent promising candidates for the treatment of neurodegenerative diseases.

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Section: Discussionmentioning

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Phenotypic and Functional Characterizations of Mesenchymal Stem/Stromal Cells Isolated From Human Cranial Bone Marrow

Yang

Lu²,

Lu³

et al. 2022

Front. Neurosci.

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“…However, tcMEPs must be recorded in rats with varying levels of paralysis to investigate the above correlation over a relatively short period. We also reported that the transplantation of rat bone marrow-derived mesenchymal stem cells (rbMSCs) or rat cranial bone-derived mesenchymal stem cells (rcMSCs) to rat models of acute SCI enables the observation of the course of improvement in paralysis over time [17]. This previous study further showed that the waveform of tcMEPs disappears immediately after SCI and reappears with the recovery of motor function within a short period of 28 days [17].…”

Section: Introductionmentioning

confidence: 91%

“…We also reported that the transplantation of rat bone marrow-derived mesenchymal stem cells (rbMSCs) or rat cranial bone-derived mesenchymal stem cells (rcMSCs) to rat models of acute SCI enables the observation of the course of improvement in paralysis over time [17]. This previous study further showed that the waveform of tcMEPs disappears immediately after SCI and reappears with the recovery of motor function within a short period of 28 days [17]. Based on these findings, in the present study, we examined the relationship between the longitudinal electrophysiological changes and recovery from paralysis after the transplantation of MSCs in an SCI rat model.…”

Section: Introductionmentioning

confidence: 99%

Longitudinal electrophysiological changes after mesenchymal stem cell transplantation in a spinal cord injury rat model

et al. 2022

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Transcranial electrically stimulated motor-evoked potentials (tcMEPs) are widely used to evaluate motor function in humans and animals. However, the relationship between tcMEPs and the recovery of paralysis remains unclear. We previously reported that transplantation of mesenchymal stem cells to a spinal cord injury (SCI) rat model resulted in various degrees of recovery from paraplegia. As a continuation of this work, in the present study, we aimed to establish the longitudinal electrophysiological changes in this SCI rat model after mesenchymal stem cell transplantation. SCI rats were established using the weight-drop method. The model rats were transvenously transplanted with two types of mesenchymal stem cells (MSCs), one derived from rat cranial bones and the other from the bone marrow of the femur and tibia bone, 24 h after SCI. A phosphate-buffered saline (PBS) group that received only PBS was also created for comparison. The degree of paralysis was evaluated over 28 days using the Basso–Beattie–Bresnahan (BBB) scale and inclined plane task score. Extended tcMEPs were recorded using a previously reported bone-thinning technique, and the longitudinal electrophysiological changes in tcMEPs were investigated. In addition, the relationship between the time course of recovery from paralysis and reappearance of tcMEPs was revealed. The appearance of the tcMEP waveform was earlier in MSC-transplanted rats than in PBS-administered rats (earliest date was 7 days after SCI). The MEP waveforms also appeared at approximately the same level on the BBB scale (average score, 11 points). Ultimately, this study can help enhance our understanding of the relationship between neural regeneration and tcMEP recording. Further application of tcMEP in regenerative medicine research is expected.

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“…In this setting, MSCs have been shown to possess regenerative capabilities, also for conditions affecting the CNS. Animal studies have revealed that MSCs can migrate toward sites of injury ( 6 ) and promote repair of myelin and neurons, thus leading to improved functional outcomes in models of central nervous diseases ( 7 , 8 ). This effect is likely mediated through different mechanisms, such as the paracrine stimulation of endogenous progenitor- and stem cells through the MSC secretome ( 9 ), mitochondria donations ( 10 ), immunomodulation ( 11 ) and transdifferentiation toward neural cell lines ( 12 ).…”

Section: Introductionmentioning

confidence: 99%

Safety and Clinical Efficacy of Mesenchymal Stem Cell Treatment in Traumatic Spinal Cord Injury, Multiple Sclerosis and Ischemic Stroke – A Systematic Review and Meta-Analysis

et al. 2022

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BackgroundMesenchymal stem cells (MSCs) is an attractive candidate in regenerative research and clinical trials have assessed their therapeutic potential in different neurological conditions with disparate etiologies. In this systematic review, we aimed to assess safety and clinical effect of MSC treatment in traumatic spinal cord injury (TSCI), multiple sclerosis (MS) and ischemic stroke (IS).MethodsA systematic search was performed 2021-12-10 in MEDLINE, EMBASE, Web of Science and Cochrane where clinical studies assessing MSC treatment in TSCI, MS or IS were included. Studies without control group were excluded for efficacy analysis, but included in the safety analysis. For efficacy, AIS score, EDSS score and mRS were used as clinical endpoints and assessed in a meta-analysis using the random effects model.FindingsOf 5,548 identified records, 54 studies were included. Twenty-six studies assessed MSC treatment in TSCI, 14 in MS and nine in IS, of which seven, seven and five studies were controlled, respectively. There were seven serious adverse events (SAEs), of which four were related to the surgical procedure and included one death due to complications following the implantation of MSCs. Three SAEs were considered directly related to the MSC treatment and all these had a transient course. In TSCI, a meta-analysis showed no difference in conversion from AIS A to C and a trend toward more patients treated with MSCs improving from AIS A to B as compared to controls (p = 0.05). A subgroup analysis performed per protocol, showed more MSC treated patients improving from AIS A to C in studies including patients within 8 weeks after injury (p = 0.04). In MS and IS, there were no significant differences in clinical outcomes between MSC treated patients and controls as measured by EDSS and mRS, respectively.InterpretationMSC-treatment is safe in patients with TSCI, MS and IS, although surgical implantation of MSC led to one fatal outcome in TSCI. There was no clear clinical benefit of MSC treatment, but this is not necessarily a proof of inefficacy due to the low number of controlled studies. Future studies assessing efficacy of MSC treatment should aim to do this in randomized, controlled studies.

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Transplantation of rat cranial bone-derived mesenchymal stem cells promotes functional recovery in rats with spinal cord injury

Cited by 17 publications

References 53 publications

Phenotypic and Functional Characterizations of Mesenchymal Stem/Stromal Cells Isolated From Human Cranial Bone Marrow

Phenotypic and Functional Characterizations of Mesenchymal Stem/Stromal Cells Isolated From Human Cranial Bone Marrow

Longitudinal electrophysiological changes after mesenchymal stem cell transplantation in a spinal cord injury rat model

Safety and Clinical Efficacy of Mesenchymal Stem Cell Treatment in Traumatic Spinal Cord Injury, Multiple Sclerosis and Ischemic Stroke – A Systematic Review and Meta-Analysis

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