Mesenchymal Stem Cells for Spinal Cord Injury: Current Options, Limitations, and Future of Cell Therapy
Abstract
:1. Introduction
2. Spinal Cord Injury
2.1. Secondary Injury
2.2. Chronic Phase and Neurodegeneration
3. Stem Cell Therapy and Appeal of MSCs
4. Secretome of MSCs
5. MSCs
5.1. Bone Marrow Mesenchymal Stem Cells (BM-MSCs)
5.2. Umbilical Cord Mesenchymal Stem Cells (UC-MSCs)
5.3. Adipose-Derived Mesenchymal Stem Cells (AD-MSCs)
5.4. Amniotic Fetal Mesenchymal Stem Cells (AF-MSCs)
6. Biomaterials and Scaffolds for Stem Cell Therapy
7. Limitations of Current Evidence and Future Directions
- The optimal therapeutic protocols regarding the preparation, type, and number of stem cells transplanted;
- The timing of transplantation and route of administration;
- The paracrine effects and their influence on functional recovery;
- The importance of biomaterials and scaffold;
- The importance of microenvironment;
- The plasticity and ability to recreate connections of neuronal cells.
- Additionally, logistics, ethical, and financial problems related to this field of research constitute a real challenge to face in order to channel basic science studies into clinical practice.
8. Conclusions
Funding
Conflicts of Interest
References
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MSC Type | Availability [83] | Invasive Procedure of Collection [83] | Cell Proliferation In Vitro [81,85] | Secretome * [79,82,87] | MSC Survival at the Injury Site After Graft [88,89] | Low Immunogenicity in the Host Tissue [84,85] | Anti-Inflammatory Effect in Injured Spinal Cord ** [84] | Glial Scar Reduction [52,80,86,90] | Axonal Regrowth/Sprouting Support [52,80,86,90,91] | Use in Pre-Clinical Studies (This Review) | Use in Clinical Trials (This Review) |
---|---|---|---|---|---|---|---|---|---|---|---|
BM-MSCs | +++ | +++ | ++ | +++ | ++ | ++ | ++ | ++ | +++ | +++ | +++ |
UC-MSCs | + | not invasive | +++ | +++ | +++ | +++ | +++ | ++ | +++ | ++ | ++ |
AD-MSCs | +++ | ++ | ++ | +++ | +++ | ++ | ++ | ++ | +++ | ++ | ++ |
AF-MSCs | + | not invasive | +++ | +++ | +++ | +++ | not reported | not reported | +++ | + | not reported |
Study | Type of Stem Cell Transplanted | Type of SCI | Animal | Administration | Scores | Adverse Reactions | Results | Cells Analysis/Findings in the Scar |
---|---|---|---|---|---|---|---|---|
Wislet-Gendebien et al. [100] | BM-MSC | In vitro study | N/A | N/A | Anti-glial fibrillary acidic protein (GFAP); anti-GLAST; anti-Tuj1; anti-NeuN; anti-SMI31; anti-MAP2ab; anti synaptophysi; anti-M2; anti-M6; RT-PCR, electrical conductivity | N/A | Neuron-like cells differentiated from Nestin + cells without the mature neuron electrical features; No differentiation in oligodendrocyte-like cells | Nestin + cells; GFAP + cells |
Deng et al. [104] | BM-MSC | Transplantation of BM MSC 2 weeks after dorsal SCI | Macaco rhesus | Intralesional | Motor and sensitive improvement (Tarlov behavior assessment), SEP, MEP | None | Motor and sensitive functions improvement (Tarlov 2-3 achieved) in treated monkeys after 3 months follow up; Improvement of SEP and MEP | NSE +, NF +, GFAP + cells |
Zurita et al. [105] | BM-MSC | BM MSC transplanted 3 months after dorsal SCI | Pigs | Intralesional | Clinical improvement (from 0 to 10 scale where 0 means paraplegia and 10 constantly useful hike), SEP, MRI | None | 3 months after transplantation improvement of motor functions (mean score of 6.20) and SEP; reduction of the centromedullary cavity | GFAP +, NF +, S100 + cells |
Hofstetter et al. [107] | BM-MSC | Iperacute (immediately after trauma) and acute (transplantation 1 week after dorsal trauma) | Lewis rat | Intralesional | Fibronectin, vimentin, laminin cells positivity; GFAP, electrical conduction | None | Markers of neuron-like cells, but no depolarization their membrane like mature neurons; No clinical benefit in the iper acute SCI group. In the acute SCI group Ab anti Nestin and GFAP of host astrocytes around and in the scar in the MSC treated population. Immature astrocytes Nestin + GFAP + with the possibility to differentiate into neuron-like cells | Neuron-like cells, host astrocytes closely connected with transplanted MSC cells, astrocyte-like cells |
Nishio et al. [108] | HUCB stem cells | Acute (1 week after dorsal trauma) | Wistar rats | Intralesional | Basso, Beattie, Bresnahan locomotor scale (BBB), MRI | None | Hindlimb recovery, reduction of cystic cavity, no detection of any double-positive cells for human mitochondria and CD34, of CD4 positive cells, no significant differences between the two groups in the number of OX-42–positive or CD8-positive cells; GAP-43–positive fibers at the epicenter significantly higher than that of the control group | CD45 and human CD14, OX-42, CD4, CD8, GAP-43, 5-HT fibers, T-positive fibers |
Pal et al. [109] | BM-MSC | Acute (1 week after dorsal trauma) | Wistar rats | Intrathecal | BBB locomotor scale, grid walk, plantar test, inclined plane; cells were tested for CD34, CD44, CD45, CD73, CD90, CD105 and HLA-DR. | None | Improved locomotor and sensory behavioral scores. Negative astroglial markers. No graft versus host immune reaction evoked by BM MSC, with the capacity to escape the immune system and be effective in wound healing | Negative astroglial markers, BM MSC |
Nemati et al. [110] | Monkeys NSC | Acute (10 days after dorsal trauma) | Macaco rhesus monkeys | Intralesional | Spontaneous motor activity, Tarlov’s scale, limb pinch test, tail pinch test, sensory test, MRI, evaluation of neural specific markers Tuj1, MAP2, GFAP, Pax6, Sox1 | None | Improvement in the sensory and motor activity, improvement in MRI | Isolated mNSCs express NSC markers such as nestin, Sox1, and Pax6 and could differentiate into mature neurons positive for MAP2 and GFAP |
Gutierrez et al. [111] | Human fetal cortex-derived neural progenitor cells (hNPCs) | Iperacute (immediately after cervical trauma) | Göttingen minipig | Intralesional | Tarlov scale, sensory evaluation in the form of a tactile stimulus to the interdigital space | None | Improvement in motor and sensitive functions, no significant decrease in neuronal density between groups; cell engraftment ranged from 12% to 31% | |
Hakim et al. [112] | BM-MSC | Acute (24 h after dorsal trauma) | Mice | Intralesional | Cells were evaluated by flow cytometry, immunohistochemistry, immunocytochemistry, proliferation assay differentiation assay, confocal microscopy and automatic cell quantification | None | MSCs transplanted downregulate genes related to cell-cycle and DNA metabolic/biosynthetic processes and upregulate genes related to immune system response, cytokine production, and phagocytosis/endocytosis; Sca1 and CD29, MHC I maintained expression; upregulated expression of CD45 and MHC II; Transplanted MSCs survived and proliferated to a low extent, no expression of Caspase-3, no differentiation into neurons or astrocytes | Transplanted MSCs express CD29, Sca1, and CD45 MHC-I and MHC-II; transplanted MSCs survive and proliferate but do not undergo apoptosis or neural differentiation |
Cao et al. [113] | NSC | Acute (10 days after dorsal trauma) | Fischer rats | Intralesional, intrathecal | Cells were evaluated by immunohistochemistry, confocal microscopy and automatic cell quantification | None | The majority of transplanted cells either differentiated into GFAP + cells or remained nestin +. No Brd-U-positive neurons or oligodendrocytes detected | GFAP+ cells, nestin+ cells, Brd-U+ cells |
Dasari et al. [114] | HUCB stem cells | Acute (1 week after dorsal trauma) | Lewis rat | Intralesional | BBB locomotor scale, cells were tested for CD44, NF200, CNPase, O1, beta III tubulin, APC, myelin basic protein caspase 3, MAP-2A&2B, confocal/fluorescence microscope, automatic cell quantification, immune blot | None | Improved locomotor and sensory behavioral scores, downregulation HUCB cellsmediated Fas and caspase | NF-200+ cells, CNPase+ cells, CD 44+ cells, co-localization of hUCB with neurons and oligodendrocytes |
Cho et al. [115] | HUCB stem cells | Acute (1 week after dorsal trauma) | Sprague-Dawley rats | Intralesional | BBB locomotor scale, SSEPs, cells were evaluated by immunoistochemistry | None | Improved locomotor and sensory behavioral scores, shortened SSEPs latencies in treated rats | HuNu and GFAP + cells, MBP + cells, beta III tubular + cells |
Khan et.al. [92] | AD-MSCs + BDNF | Acute (1 week after lumbar trauma) | Beagle dogs | Intralesional | BBB locomotor scale, cells were tested for Tuj-1, NF, GAP-43, GFAP, Nestin, COX2, TNFa, IL6, STAT3, IL-10, HO-1, BDNF | None | Significant improvement in hindlimb functions, with a higher BBB score | Increase in neuroregeneration, higher expression of Tuj-1, NF-M, and GAP-43, decreased expression of the inflammatory markers interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), and an increased expression of interleukin-10 (IL-10). H&E staining showed more reduced intraparenchymal fibrosis |
Ryu et. al. [88] | BM-MSC, AD-MSC, UCB MSC, Wharton’s jelly-derived MSC | Acute (1 week after lumbar trauma) | Beagle dogs | Intralesional | Olby score and Revised Modified Talov scale, BBB locomotor scale, confocal/fluorescence microscope. Immunoistochemistry | None | Significant differences of neurologic recovery in MSCs groups at 2 weeks following MSC transplantation. Purposeful hind limb motion of all dogs in the MSCs groups. No significant differences observed among the MSCs groups. UCB-derived MSCs (UCSCs) induced more nerve regeneration and anti-inflammation activity | Some MSCs expressed markers for neurons (NF160), neuronal nuclei (NeuN) and astrocytes (GFAP). NF160- and NeuN-positive neurons were found, GFAP-positive reactive astrocytes were observed more often in the control group than in MSCs groups. Lesion sizes were smaller, and fewer microglia and reactive astrocytes were found in the spinal cord epicenter of all MSC groups |
Penha et.al. [93] | BM-MSC | Acute (10 days after dorsal or lumbar trauma) | Dogs | Intralesional | Clinical evaluation, MRI images | None | No changes at the MSC administration site into the spinal cord. Progressive recovery of the panniculus reflex and diminished superficial and deep pain response. Conscious reflex recovery occurred simultaneously with moderate improvement in intestine and urinary bladder functions | N/A |
Kim et.al. [94] | AD-MSCs | Acute (1 week after dorsal or lumbar trauma) | Dogs | Intralesional | Clinical improvement: full recovery (normal neurologic state; grade 0), improved (regained deep pain perception (DPP) and recovery of ambulation, but still had mild ataxia; grade 1–2) and unsuccessful (did not regain DPP or the ability to walk without support; grade 3–5) | None | Clinical improvement (55.6% of the dogs were in full recovery, 22.2% showed improved outcomes and 22.2% had unsuccessful recovery) | N/A |
Kim et.al. [95] | AD-MSCs | Iperacute (immediately after lumbar trauma) | Beagle dogs | Intravenous | Revised Tarlov scale, gait analysis, cells were evaluated by western blot | None | Significant enhanced motor function in AD-MSCs group compared with those in the control group at 7 days post treatment | The levels of GFAP, and GalCa were increased in the AD-MSC group, β3-tubulin levels were increased, COX-2, IL-6, and TNFα levels were significantly decreased; 3-NT level was significantly decreased, the level of 4-HNE was significantly decreased; the level of PC was significantly decreased |
Study | Type of SCI | Administration | n of Transplanted Cells | Transplanted Cells Type | Scores | Adverse Reactions | Results |
---|---|---|---|---|---|---|---|
Jeon et al. [116] | 10 acute SCI patients | Intrathecal | 8 × 106 cells | Autologous MSCs | ASIA, Frankel score, EMG, SEP, MRI | None | Improvement in ASIA score, EMG, and SEP; improvement in MRI imaging |
Dai et al. [118] | 40 human patients; chronic and complete cervical SCI (AIS A) | Perilesional | Suspension with 8 × 105 cells/microl | Autologous BM-MSCs expanded in culture | AIS, ASIA, residual urinary volume, EMG, MRI | None | 45% AIS A to B; ASIA total scores were 31.6 prior and 43.1 after treatment (p = 0.01); preoperative urinary volume 235 mL to postop volume 173 mL (p = 0.01), improvement also in EMG and MRI |
El Kheir et al. [119] | 70 human patients; chronic complete cervical or thoracic SCI | Intrathecal | 2 × 106 cells/kg | Autologous BM-MSCs | AIS, ASIA, MRI, SEP | None | AIS conversion from AIS A to AIS B or C and from AIS B to AIC C; Improvement in ASIA score, SEP and in MRI. Higher improvement in the thoracic than in the cervical SCI group |
Geffner 2008 [120] | 8 human patients (4 acute SCI, 4 chronic SCI) | Directly into the spinal cord, directly into the spinal canal, and intravenous | / | Autologous BM-MSCs | ASIA, Barthel, Frankel Ashworth score, residual urinary volume, MRI | None | Improvement in all of the parameters |
Karamouzian et al. [121] | 11 human patients with acute or subacute (2-8 weeks after trauma) SCI | Intrathecal | 7 × 105 to 1.2 × 106 cells | Autologous BM-MSCs | ASIA (12-33 months follow up) | None | Improvement in the ASIA score but the score was not statistically significant (p = 0.095) |
Mendonca et al. [122] | 14 human patients with chronic thoraco -lumbar SCI | Intralesional | 5 × 106 cells/cm3 | BM-derived MSCs expanded in culture | ASIA, SEP, MRI, urodinamic, AIS | None | AIS A to B or C; incomplete injury; urinary function improved in 9 subjects, SEP improved in 1 subject |
Park et al. [123] | 6 human patients with cervical SCI treated at 72 h after trauma | Intralesional | 2 × 108 cells | Autologous BM-MSCs | Frankel, AIS, MRI | None | AIS A to B/C; improved MRI |
Sykova et al. [124] | 20 human patients with complete SCI transplanted from 10 to 467 days after trauma | Intra arterial vs. intra venous | 89.7 +/− 70.7 × 106 cells | Autologous BM-MSCs | Frankel, AIS, ASIA, SEP, MRI | None | Not significant results at 3–6–12 months follow-up; however, there was a positive trend |
Pal et al. [125] | 30 human patients with complete cervical or thoracic SCI | Intrathecal | 1 × 106 cells | Autologous BM-MSCs expanded in culture | ASIA, Barthel, SSEP, MEP, NCV, MRI | None | No significant results in ASIA score; variable patterns of recovery (especially in bladder functions), no significant variations in SSEP, MEP, NCV. Improved MRI |
Moviglia et al. [126] | 2 human patients with cervical and thoracic chronic SCI | Intra arterial | 5 × 108 to 1 × 109 cells | Autologous BM-MSCs | SSEP, MEP, MRI, clinical examination | None | Improvement in all of the parameters |
ClinicalTrials.Gov Identifier | Title | MSC Type | Enrolled Subjects | Phase(s) | I End Point | II End Point | Date of Completion | Site of Administration | Intervention | Status |
---|---|---|---|---|---|---|---|---|---|---|
NCT03521336 | Intrathecal transplantation of UC-MSC in patients with sub-acute spinal cord injury | UC-MSCs | 130 | II | ASIA score | IANR-SCIRFS score; EMG; residual urine | Dec 2022 | Intrathecal | Allogeneic UC-MSCs | Recruiting |
NCT03308565 | Adipose stem cells for traumatic spinal cord injury | AD-MSCs | 10 | I | Acute adverse event | ASIA; MEPs; SSEPs; MRI; functional changes | Nov 2023 | Intrathecal | Autologous AD-MSCs | Recruiting |
NCT03225625 | Stem cell spinal cord injury exoskeleton and virtual reality treatment study | BM-MSCs | 40 | N/A | ASIA score | ANS function; general well-being | Jul 2022 | Paraspinal; intravenous; intranasal | Autologous BM-MSCs | Recruiting |
NCT02917291 | Safety and preliminary efficacy of FAB117-HC in patients with acute traumatic spinal cord injury | AD- MSCs | 46 | I/II | Safety | ISNC-SCI; SCIM III; SSEPs; MEPs | Jan 2020 | Intramedullary | Autologous AD-MSCs | Recruiting |
NCT01676441 | Safety and efficacy of autologous mesenchymal stem cells in chronic spinal cord injury | BM-MSCs | 32 | II/III | Treatment | / | Dec 2020 | Intramedullary | Autologous BM-MSC | Recruiting |
NCT03505034 | Intrathecal transplantation of UC-MSC in patients with late stage of chronic spinal cord injury | UC-MSCs | 43 | II | ASIA score | IANR-SCIRFS score; EMG; residual urine | Dec 2021 | Intrathecal | Umbilical cord mesenchymal stem cells | Recruiting |
NCT02574572 | Autologous mesenchymal stem cell transplantation in cervical chronic and complete spinal cord injury | BM-MSCs | 10 | I | N of participants with treatment-related adverse events as assessed by MRI | ASIA score, ASIA impairment scale, improvement in sensorial mapping and neuropathic pain | Jun 2020 | Intralesional | Autologous BM-MSC | Recruiting |
NCT03521323 | Intrathecal transplantation of UC-MSC in patients with early stage of chronic spinal cord injury | UC-MSCs | 66 | I/II | ASIA score | IANR-SCIRFS score; EMG; residual urine | Dec 2021 | Intrathecal | Umbilical cord mesenchymal stem cells | Recruiting |
NCT02574585 | Autologous mesenchymal stem cell transplantation in thoracolumbar chronic and complete spinal cord injury | BM-MSCs | 40 | II | N of participants with treatment-related adverse events as assessed by MRI SCI | ASIA score, AIS score, improving in sensorial mapping and neuropathic pain | Jan 2022 | Percutaneous | Autologous BM-MSC | Not yet recruiting |
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Cofano, F.; Boido, M.; Monticelli, M.; Zenga, F.; Ducati, A.; Vercelli, A.; Garbossa, D. Mesenchymal Stem Cells for Spinal Cord Injury: Current Options, Limitations, and Future of Cell Therapy. Int. J. Mol. Sci. 2019, 20, 2698. https://doi.org/10.3390/ijms20112698
Cofano F, Boido M, Monticelli M, Zenga F, Ducati A, Vercelli A, Garbossa D. Mesenchymal Stem Cells for Spinal Cord Injury: Current Options, Limitations, and Future of Cell Therapy. International Journal of Molecular Sciences. 2019; 20(11):2698. https://doi.org/10.3390/ijms20112698
Chicago/Turabian StyleCofano, Fabio, Marina Boido, Matteo Monticelli, Francesco Zenga, Alessandro Ducati, Alessandro Vercelli, and Diego Garbossa. 2019. "Mesenchymal Stem Cells for Spinal Cord Injury: Current Options, Limitations, and Future of Cell Therapy" International Journal of Molecular Sciences 20, no. 11: 2698. https://doi.org/10.3390/ijms20112698