Spinal Cord Injury and Stem Cells

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Human umbilical cord blood stem cells for spinal cord injury: early transplantation results in better local angiogenesis

Regen Med. 2013 May;8(3):271-81
Authors: Ning G, Tang L, Wu Q, Li Y, Li Y, Zhang C, Feng S

AIM: We aim to explore the repair mechanism after the transplantation of CD34(+) human umbilical cord blood cells (HUCBCs) in traumatic spinal cord injury (SCI) in rats.

MATERIALS & METHODS: Wistar rats with SCI were randomly divided into three groups: DMEM injection (group A); CD34(+) HUCBC transplantation on the first day after injury (group B); and CD34(+) HUCBC transplantation on the sixth day after injury (group C). The Basso, Beattie and Bresnahan scores were used to evaluate motor behavior. At the injured site, the infarct size, blood vessel density, and survival and neural differentiation of transplanted cells were analyzed.

RESULTS: It was found that the Basso, Beattie and Bresnahan score in group B was significantly higher than other groups (p < 0.05), and the infarct size and blood vessel density at the injured site were significantly different (p < 0.01). However, the transplanted cells survived at least 3 weeks at the injured site, but did not differentiate into neural cells. CONCLUSION: These results suggested transplantation of CD34(+) HUCBCs during the acute phase could promote the functional recovery better than during the subacute phase after SCI by raising blood vessel density, suggesting the possible clinical application for the treatment of spinal injury. PMID: 23627822 [PubMed - indexed for MEDLINE]

Clinical analysis of the treatment of spinal cord injury with umbilical cord mesenchymal stem cells

Cytotherapy. 2013 Feb;15(2):185-91
Authors: Liu J, Han D, Wang Z, Xue M, Zhu L, Yan H, Zheng X, Guo Z, Wang H

BACKGROUND AIMS: The purpose of this study was to observe the clinical effect and safety of umbilical cord mesenchymal stem cells (UC-MSCs) in treating spinal cord injury (SCI) by intrathecal injection.

METHODS: From January 2008 to October 2010, we treated 22 patients with SCI with UC-MSCs by intrathecal injection; dosage was 1 × 10(6) cells/kg body weight once a week given four times as a course. Four patients received two courses, one patient received three courses and all other patients received one course. American Spinal Injury Association scoring system and International Association of Neurorestoratology Spinal Cord Injury Functional Rating Scale were used to evaluate neural function and ability to perform activities of daily living.

RESULTS: Treatment was effective in 13 of 22 patients; nine patients had no response. Among patients with incomplete SCI, the response to treatment was 81.25%; there was no response to treatment among six patients with complete SCI. Five patients with a response to treatment received two to three courses of therapy, and effects in these patients were further enhanced. In most patients in whom treatment was effective, motor or sensory functions, or both, were improved, and bowel and bladder control ability was improved. In 22 patients 1 month after therapy, algesia, tactile sensation, motion and activity of daily living scale were significantly improved (P < 0.01). During therapy, common adverse effects were headache (one case) and low back pain (one cases); these disappeared within 1-3 days. No treatment-related adverse events occurred during a follow-up period ranging from 3 months to 3 years. CONCLUSIONS: UC-MSC therapy by intrathecal injection is safe and can improve neurologic function and quality of life in most patients with incomplete SCI. PMID: 23321330 [PubMed - indexed for MEDLINE]

Transplantation of human umbilical cord blood or amniotic epithelial stem cells alleviates mechanical allodynia after spinal cord injury in rats

Cell Transplant. 2013;22(9):1577-90
Authors: Roh DH, Seo MS, Choi HS, Park SB, Han HJ, Beitz AJ, Kang KS, Lee JH

Stem cell therapy is a potential treatment for spinal cord injury (SCI), and a variety of different stem cell types have been grafted into humans suffering from spinal cord trauma or into animal models of spinal injury. Although several studies have reported functional motor improvement after transplantation of stem cells into injured spinal cord, the benefit of these cells for treating SCI-induced neuropathic pain is not clear. In this study, we investigated the therapeutic effect of transplanting human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) or amniotic epithelial stem cells (hAESCs) on SCI-induced mechanical allodynia (MA) and thermal hyperalgesia (TH) in T13 spinal cord hemisected rats. Two weeks after SCI, hUCB-MSCs or hAESCs were transplanted around the spinal cord lesion site, and behavioral tests were performed to evaluate changes in SCI-induced MA and TH. Immunohistochemical and Western blot analyses were also performed to evaluate possible therapeutic effects on SCI-induced inflammation and the nociceptive-related phosphorylation of the NMDA NR1 receptor subunit. While transplantation of hUCB-MSCs showed a tendency to reduce MA, transplantation of hAESCs significantly reduced MA. Neither hUCB-MSC nor hAESC transplantation had any effect on SCI-induced TH. Transplantation of hAESCs also significantly reduced the SCI-induced increase in NMDA receptor NR1 subunit phosphorylation (pNR1) expression in the spinal cord. Both hUCB-MSCs and hAESCs reduced the SCI-induced increase in spinal cord expression of the microglial marker, F4/80, but not the increased expression of GFAP or iNOS. Taken together, these findings demonstrate that the transplantation of hAESCs into the injured spinal cord can suppress mechanical allodynia, and this effect seems to be closely associated with the modulation of spinal cord microglia activity and NR1 phosphorylation.

PMID: 23294734 [PubMed – in process]

A combination of taxol infusion and human umbilical cord mesenchymal stem cells transplantation for the treatment of rat spinal cord injury

Brain Res. 2012 Oct 24;1481:79-89
Authors: Zhilai Z, Hui Z, Anmin J, Shaoxiong M, Bo Y, Yinhai C

BACKGROUND AND PURPOSE: Studies have shown that the administration of Taxol, an anti-cancer drug, inhibited scar formation, promoted axonal elongation and improved locomotor recovery in rats after spinal cord injury (SCI). We hypothesized that combining Taxol with another promising therapy, transplantation of human umbilical mesenchymal stem cells (hUCMSCs), might further improve the degree of locomotor recovery. The present study examined whether Taxol combined with transplantation of hUCMSCs would produce synergistic effects on recovery and which mechanisms were involved in the effect.

METHODS: A total of 32 rats subjected to SCI procedures were assigned to one of the following four treatment groups: phosphate-buffered saline (PBS, control), hUCMSCs, Taxol, or Taxol+hUCMSCs. Immediately after injury, hUCMSCs were transplanted into the injury site and Taxol was administered intrathecally for 4 weeks. Locomotor recovery was evaluated using the Basso, Beattie and Bresnahan locomotor (BBB) rating scale. Survival of the transplanted human cells and the host glial reaction in the injured spinal cord were studied by immunohistochemistry.

RESULTS: Treatment with Taxol, hUCMSCs or Taxol+hUCMSCs reduced the extent of astrocytic activation, increased axonal preservation and decreased the number of caspase-3(+) and ED-1(+) cells, but these effects were more pronounced in the Taxol+hUCMSCs group. Behavioral analyses showed that rats in the Taxol+hUCMSCs group showed better motor performance than rats treated with hUCMSCs or Taxol only.

CONCLUSIONS: The combination of Taxol and hUCMSCs produced beneficial effects in rats with regard to functional recovery following SCI through the enhancement of anti-inflammatory, anti-astrogliosis, anti-apoptotic and axonal preservation effects.

PMID: 22960115 [PubMed – indexed for MEDLINE]

Schwann cell-like remyelination following transplantation of human umbilical cord blood (hUCB)-derived mesenchymal stem cells in dogs with acute spinal cord injury

J Neurol Sci. 2011 Jan 15;300(1-2):86-96
Authors: Lee JH, Chung WH, Kang EH, Chung DJ, Choi CB, Chang HS, Lee JH, Hwang SH, Han H, Choe BY, Kim HY

Human umbilical cord blood derived mesenchymal stem cells (hUCB-MSCs) have significant therapeutic potential in cell-based therapies following spinal cord injury (SCI). To evaluate this potential, we conducted our preliminary investigations on the remyelination of injured spinal cords with hUCB-MSC transplantations and we observed its long term effects on dogs with SCI. Of the ten injured dogs, seven were transplanted with hUCB-MSCs 1 week after SCI, whereas the remaining three dogs were not transplanted. Two transplanted dogs died over the first month after transplantation because of urinary tract infection, bedsores and sepsis. The SCI dogs showed no improvement in motor and sensory functions and their urinary dysfunction persisted until they were euthanized (from 3 months to 1 year) while hind-limb recovery in 4 dogs among the five transplanted dogs was significantly improved. In the recovered dogs, functional recovery was sustained for three years following transplantation. Histological results from five transplanted dogs showed that many axons were remyelinated by P0-positive myelin sheaths after transplantation. Our results suggest that transplantation of hUCB-derived MSCs may have beneficial therapeutic effects. Furthermore, histological results provided the first in vivo evidence that hUCB-MSCs are able to enhance the remyelination of peripheral-type myelin sheaths following SCI.

PMID: 21071039 [PubMed – indexed for MEDLINE]

Functional recovery in acute traumatic spinal cord injury after transplantation of human umbilical cord mesenchymal stem cells

Crit Care Med. 2010 Nov;38(11):2181-9
Authors: Hu SL, Luo HS, Li JT, Xia YZ, Li L, Zhang LJ, Meng H, Cui GY, Chen Z, Wu N, Lin JK, Zhu G, Feng H

OBJECTIVE: Spinal cord injury results in loss of neurons, degeneration of axons, formation of glial scar, and severe functional impairment. Human umbilical cord mesenchymal stem cells can be induced to form neural cells in vitro. Thus, these cells have a potential therapeutic role for treating spinal cord injury.

DESIGN AND SETTING: Rats were randomly divided into three groups: sham operation group, control group, and human umbilical cord mesenchymal stem cell group. All groups were subjected to spinal cord injury by weight drop device except for sham group.

SUBJECTS: Thirty-six female Sprague-Dawley rats.

INTERVENTIONS: The control group received Dulbecco’s modified essential media/nutrient mixture F-12 injections, whereas the human umbilical cord mesenchymal stem cell group undertook cells transplantation at the dorsal spinal cord 2 mm rostrally and 2 mm caudally to the injury site at 24 hrs after spinal cord injury.

MEASUREMENTS: Rats from each group were examined for neurologic function and contents of brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, and neurotrophin-3. Survival, migration, and differentiation of human umbilical cord mesenchymal stem cells, regeneration of axons, and formation of glial scar were also explored by using immunohistochemistry and immunofluorescence.

MAIN RESULTS: Recovery of hindlimb locomotor function was significantly enhanced in the human umbilical cord mesenchymal stem cells grafted animals at 5 wks after transplantation. This recovery was accompanied by increased length of neurofilament-positive fibers and increased numbers of growth cone-like structures around the lesion site. Transplanted human umbilical cord-mesenchymal stem cells survived, migrated over short distances, and produced large amounts of glial cell line-derived neurotrophic factor and neurotrophin-3 in the host spinal cord. There were fewer reactive astrocytes in both the rostral and caudal stumps of the spinal cord in the human umbilical cord-mesenchymal stem cell group than in the control group.

CONCLUSIONS: Treatment with human umbilical cord mesenchymal stem cells can facilitate functional recovery after traumatic spinal cord injury and may prove to be a useful therapeutic strategy to repair the injured spinal cord.

PMID: 20711072 [PubMed – indexed for MEDLINE]

Transplantation of umbilical cord blood stem cells for treating spinal cord injury

Stem Cell Rev. 2011 Mar;7(1):181-94
Authors: Park DH, Lee JH, Borlongan CV, Sanberg PR, Chung YG, Cho TH

Spinal cord injury (SCI) develops primary and secondary damage to neural tissue and this often results in permanent disability of the motor and sensory functions. However, there is currently no effective treatment except methylprednisolone, and the use of methylprednisolone has also been questioned due to its moderate efficacy and the drug’s downside. Regenerative medicine has remarkably developed since the discovery of stem cells, and many studies have suggested the potential of cell-based therapies for neural injury. Especially, the therapeutic potential of human umbilical cord blood cells (hUCB cells) for intractable neurological disorders has been demonstrated using in vitro and vivo models. The hUCB cells are immune naïve and they are able to differentiate into other phenotypes, including the neural lineage. Their ability to produce several neurotropic factors and to modulate immune and inflammatory reactions has also been noted. Recent evidence has emerged suggesting alternative pathways of graft-mediated neural repair that involve neurotrophic effects. These effects are caused by the release of various growth factors that promote cell survival, angiogenesis and anti-inflammation, and this is all aside from a cell replacement mechanism. In this review, we present the recent findings on the stemness properties and the therapeutic potential of hUCB as a safe, feasible and effective cellular source for transplantation in SCI. These multifaceted protective and restorative effects from hUCB grafts may be interdependent and they act in harmony to promote therapeutic benefits for SCI. Nevertheless, clinical studies with hUCB are still rare because of the concerns about safety and efficiency. Among these concerns, the major histocompatibility in allogeneic transplantation is an important issue to be addressed in future clinical trials for treating SCI.

PMID: 20532836 [PubMed – indexed for MEDLINE]

Percutaneous transplantation of human umbilical cord blood-derived multipotent stem cells in a canine model of spinal cord injury/

J Neurosurg Spine. 2009 Dec;11(6):749-57
Authors: Lee JH, Chang HS, Kang EH, Chung DJ, Choi CB, Lee JH, Hwang SH, Han H, Kim HY

OBJECT: The authors describe a method for percutaneous transplantation of human umbilical cord blood (hUCB)-derived multipotent stem cells (MSCs) under fluoroscopic guidance. The investigators then tested whether percutaneous transplantation of hUCB-derived MSCs improved neurological functional recovery after acute spinal cord injury (SCI).

METHODS: The authors induced SCI in 10 dogs by percutaneous balloon compression. The 10 injured dogs were assigned randomly to the following groups (2 dogs each): Group 1, evaluated 2 weeks after sham transplantation; Group 2, evaluated 2 weeks after transplantation; Group 3, evaluated 4 weeks after sham transplantation; Group 4, evaluated 4 weeks after transplantation; and Group 5, evaluated 4 weeks after multispot transplantations. The dogs with sham transplantation (Groups 1 and 3) received the same volume of saline, as a control. A spinal needle was advanced into the spinal canal, and the investigators confirmed that the end of the spinal needle was located in the ventral part of spinal cord parenchyma by using contrast medium under fluoroscopic guidance. The hUCB-derived MSCs were transplanted into the cranial end of the injured segment in 6 injured dogs at 7 days after SCI.

RESULTS: Two dogs in Group 2 showed no improvement until 2 weeks after transplantation. Three of 4 dogs (Groups 4 and 5) that received cellular transplants exhibited gradual improvement in hindlimb locomotion from 3 weeks after cell transplantation. The CM-DiI-labeled hUCB-derived MSCs were observed in the spinal cord lesions at 4 weeks posttransplantation and exerted a significant beneficial effect by reducing cyst and injury size. The transplanted cells were positive for NeuN, glial fibrillary acidic protein, and von Willebrand factor.

CONCLUSIONS: The percutaneous transplantation technique described here can be easily performed, and it differs from previous techniques by avoiding surgical exposure and allowing cells to be more precisely transplanted into the spinal cord. This technique has many potential applications in the treatment of human SCI by cell transplantation. The results also suggest that transplantation of hUCB-derived MSCs may have therapeutic effects that decrease cavitation for acute SCI.

PMID: 19951029 [PubMed – indexed for MEDLINE]

Human umbilical cord blood stem cells upregulate matrix metalloproteinase-2 in rats after spinal cord injury

Neurobiol Dis. 2009 Oct;36(1):200-12
Authors: Veeravalli KK, Dasari VR, Tsung AJ, Dinh DH, Gujrati M, Fassett D, Rao JS

Matrix metalloproteinases (MMPs) are a large family of proteolytic enzymes involved in inflammation, wound healing and other pathological processes after neurological disorders. MMP-2 promotes functional recovery after spinal cord injury (SCI) by regulating the formation of a glial scar. In the present study, we aimed to investigate the expression and/or activity of several MMPs, after SCI and human umbilical cord blood mesenchymal stem cell (hUCB) treatment in rats with a special emphasis on MMP-2. Treatment with hUCB after SCI altered the expression of several MMPs in rats. MMP-2 is upregulated after hUCB treatment in spinal cord injured rats and in spinal neurons injured either with staurosporine or hydrogen peroxide. Further, hUCB induced upregulation of MMP-2 reduced formation of the glial scar at the site of injury along with reduced immunoreactivity to chondroitin sulfate proteoglycans. Blockade of MMP-2 activity in hUCB cocultured injured spinal neurons reduced the protection offered by hUCB which indicated the involvement of MMP-2 in the neuroprotection offered by hUCB. Based on these results, we conclude that hUCB treatment after SCI upregulates MMP-2 levels and reduces the formation of the glial scar thereby creating an environment suitable for endogenous repair mechanisms.

PMID: 19631747 [PubMed – indexed for MEDLINE]

Human umbilical cord mesenchymal stem cells and the treatment of spinal cord injury

Chin Med J (Engl). 2009 Jan 20;122(2):225-31
Authors: Cao FJ, Feng SQ

OBJECTIVE: To review the recent studies about human umbilical cord mesenchymal stem cells (hUCMSCs) and advances in the treatment of spinal cord injury. Data sources Published articles (1983 – 2007) about hUCMSCs and spinal cord injury were selected using Medline. Study selection Articles selected were relevant to development of mesenchymal stem cells (MSCs) for transplantation in spinal cord injury therapy. Of 258 originally identified articles 51 were selected that specifically addressed the stated purpose.

RESULTS: Recent work has revealed that hUCMSCs share most of the characteristics with MSCs derived from bone marrow and are more appropriate to transplantation for cell based therapies.

CONCLUSIONS: Human umbilical cord could be regarded as a source of MSCs for experimental and clinical needs. In addition, as a peculiar source of stem cells, hUCMSCs may play an important role in the treatment of spinal cord injury.

PMID: 19187651 [PubMed – indexed for MEDLINE]

Transplantation of human umbilical cord stem cells improves neurological function recovery after spinal cord injury in rats

Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2004 Feb;26(1):38-42
Authors: Li HJ, Liu HY, Zhao ZM, Lu SH, Yang RC, Zhu HF, Cai YL, Zhang QJ, Han ZC

OBJECTIVE: To study whether intraspinally transplanted human cord blood CD34+ cells can survive, differentiate, and improve neurological functional recovery after spinal cord injury in rats.

METHODS: Rats were randomly divided into two groups. One group of rats was subjected to spinal cord left-hemisection and transplanted with human cord blood CD34+ cells labeled by bromodeoxyuridine (BrdU); The other group was carried by left-hemisection with injection of PBS (control group). The neurological function was determined before and 24 h, 1, 2, 3 and 4 weeks after spinal cord injury and cell transplantation using the modified Tarlov score. The distribution and differentiation of transplanted human cord blood cells in vivo in rat spinal cord were evaluated by histological and immnuhistochemical analysis.

RESULTS: Functional recovery determined by modified Tarlov score was significantly improved in the group receiving human cord blood CD34+ cells compared with the control group (P < 0.05). Moreover, human cord blood CD34+ cells were found to survive in rat spinal cord microenvironment, with the expression of the neural nuclear specific protein (NeuN) in 2% BrdU-reactive human cells and of the astrocytic specific protein glial fibrillary acidic protein (GFAP) in 7% BrdU-reactive human cells. CONCLUSIONS: Intraspinally administered human cord blood CD34+ cells can survive, differentiate, and improve functional recovery after spinal cord injury in rats. Transplantation of human cord blood cells may provide a novel strategy for the treatment of neural injury. PMID: 15052772 [PubMed - indexed for MEDLINE]

Human umbilical cord blood stem cells infusion in spinal cord injury: engraftment and beneficial influence on behavior

J Hematother Stem Cell Res. 2003 Jun;12(3):271-8
Authors: Saporta S, Kim JJ, Willing AE, Fu ES, Davis CD, Sanberg PR

The use of human umbilical cord blood (hUCB)–a rich source of nonembryonic or adult stem cells–has recently been reported to ameliorate behavioral consequences of stroke. In this study, we tested whether human cord blood leukocytes also ameliorate behavioral impairments of spinal cord injury. Rats were divided into five groups: (1) laminectomy (without spinal cord injury) only; (2) laminectomy + cord blood infusion; (3) spinal cord injury + cord blood infused 1 day post injury; (4) spinal cord injury + cord blood infused 5 days post injury; and (5) spinal cord injury only. Spinal cord injury was induced by compressing the spinal cord for 1 min with an aneurysm clip calibrated to a closing pressure of 55 g. Open-field behavior was assessed 1, 2, and 3 weeks after intravenous injection of prelabeled human cord blood cells. Open-field test scores of spinal cord injured rats treated with human cord blood at 5 days were significantly improved as compared to scores of rats similarly injured but treated at day 1 as well as the otherwise untreated injured group. The results suggest that cord blood stem cells are beneficial in reversing the behavioral effects of spinal cord injury, even when infused 5 days after injury. Human cord blood-derived cells were observed in injured areas, but not in noninjured areas, of rat spinal cords, and were never seen in corresponding areas of spinal cord of noninjured animals. The results are consistent with the hypothesis that cord blood-derived stem cells migrate to and participate in the healing of neurological defects caused by traumatic assault.

PMID: 12857368 [PubMed – indexed for MEDLINE]