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   Table of Contents      
REVIEW ARTICLE
Year : 2018  |  Volume : 4  |  Issue : 3  |  Page : 124-127

Wharton' jelly mesenchymal stromal cell therapy for ischemic brain injury


1 Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli County, Taiwan
2 Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Miaoli County, Taiwan
3 Regenerative Medicine Research Group, Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli County, Taiwan
4 Department of Obstetrics and Gynecology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

Date of Submission27-Jul-2018
Date of Acceptance10-Sep-2018
Date of Web Publication09-Oct-2018

Correspondence Address:
Dr. Yun Wang
Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli County
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/bc.bc_16_18

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  Abstract 

Increasing evidence have supported that Wharton's jelly mesenchymal stem cell (WJ-MSCs) have immunomodulatory and protective effects against several diseases including kidney, liver pathologies, and heart injury. Few in vitro studies have reported that WJ-MSCs reduced inflammation in hippocampal slices after oxygen–glucose deprivation. We recently reported the neuroprotective effects of human WJ-MSCs (hWJ-MSCs) in rats exposed to a transient right middle cerebral artery occlusion. hWJ-MSCs transplantation significantly reduced brain infarction and microglia activation in the penumbra leading with a significant reduction of neurological deficits. Interestingly, the grafted hWJ-MSCs in the ischemic core were mostly incorporated into IBA1 (+) cells, suggesting that hWJ-MSCs were immunorejected by the host. The immune rejection of hWJ-MSCs was reduced in after cyclosporine A treatment. Moreover, the glia cell line-derived neurotrophic factor expression was significantly increased in the host brain after hWJ-MSCs transplantation. In conclusion, these results suggest that the protective effect of hWJ-MSCs may be due to the secretion of trophic factors rather than to the survival of grafted cells. This paper is a review article. Referred literature in this paper has been listed in the references section. The data sets supporting the conclusions of this article are available online by searching various databases, including PubMed. Some original points in this article come from the laboratory practice in our research center and the authors' experiences.

Keywords: Cyclosporin, stroke, Wharton's jelly derived-mesenchymal stromal cells, xenotransplantation


How to cite this article:
Wu KJ, Yu SJ, Chiang CW, Lee YW, Yen B L, Hsu CS, Kuo LW, Wang Y. Wharton' jelly mesenchymal stromal cell therapy for ischemic brain injury. Brain Circ 2018;4:124-7

How to cite this URL:
Wu KJ, Yu SJ, Chiang CW, Lee YW, Yen B L, Hsu CS, Kuo LW, Wang Y. Wharton' jelly mesenchymal stromal cell therapy for ischemic brain injury. Brain Circ [serial online] 2018 [cited 2020 Jan 19];4:124-7. Available from: http://www.braincirculation.org/text.asp?2018/4/3/124/242905


  Introduction Top


Stroke is the second leading cause of death worldwide behind heart diseases.[1] Only a drug is currently available for the treatment of stroke, tPA, but the restricted time window of application and the severe side effects limit its use. Most of alternative pharmacological therapies developed have not been successful. Stem cell therapies are promising strategies for stroke.


  Neuroprotective Effects of Umbilical Cord Wharton's Jelly Mesenchymal Stem Cells Top


The umbilical cord Wharton's Jelly mesenchymal stem cells (WJ-MSCs) have been shown to secrete both trophic and immunomodulatory proprieties.[2],[3] Indeed, lower levels of interferon-γ receptor 1 and CXCR3 receptors and higher constitutive expression of BDNF compared to bone marrow-MSCs have been reported.[3] In addition, the secretome of WJ-MSCs can stimulate the endogenous repair mechanisms promoting the neurodifferentiation of neural progenitor cells.[4],[5] Moreover, the protective effects of WJ-MSCs can also be associated to the suppression of apoptosis, reported in an in vitro study, and increase of survival and decrease of vascular atrophy in an ex vivo hippocampal CA1 region after oxygen–glucose deprivation.[6],[7] Despite few in vivo studies involving the treatment of brain diseases with WJ-MSCs, a rat stroke model showed that both intracerebral and intravenous transplantation of WJ-MSCs improved neurological functions.[8] Furthermore, WJ-MSCs-derived dopaminergic neurons improved the rotation behavior in a Parkinson's disease (PD) animal model.[9] Similarly, in a traumatic brain injury (TBI) model, the intracerebral transplantation of WJ tissue reduced brain edema and increased MAP2 (+) cells in the injured cortex associated with the improvement of neurological function and promotion of cognitive recovery.[10] Therefore, these results suggest that WJ-MSCs transplantation could be a novel potential strategy for the treatment of neurodegenerative diseases. An advantage of paramount importance in the WJ-MSCs transplantation is that the immunosuppressive medication is not necessary due to their immunomodulatory proprieties as shown in animal models of PD, TBI, epilepsy, spinal cord injury, hypoxic-ischemic encephalopathy, and stroke.[10],[11],[12],[13],[14],[15] However, there is the necessity to find an adequate assessment of the grafted hWJ-MSC survival. In this context, chloromethyl benzamide 1,1'-dioctadecyl-3, 3, 3'3'-tetramethylindocarbocyanine perchlorate (CM-Dil)-labeled immunofluorescence has been used to stain the human WJ-MSCs (hWJ-MSCs), but this marker can be transferred among the cells by phagocytosis of dying cells making the survival measurement of grafted hWJ-MSCs inconsistent.[16],[17]


  Transplantation of hWJ-MSCs Reduces Ischemic Brain Injury Top


The neuroprotective effect of hWJ-MSCs transplant has been examined in a rat model of stroke (Wu et al., Cell Transplantation, 2018, in press). In this study, hWJ-MSCs were grafted into the cerebral cortex of experimental rats. Stroke was introduced by a transient (60 min) distal middle cerebral artery occlusion. Transplantation of hWJ-MSCs significantly reduced brain infarction, improved neurological function, and decreased neuroinflammation at 3 and 5 days after stroke surgery. These data suggest that transplantation of hMJ-MSCs reduces ischemic brain injury.


  Functional Recovery Does not Correlate With the Survival of Grafted Cells in Stroke Brain Top


Microglia can phagocytize CM-DiI-labeled grafted cells at the site of transplantation (Wu et al., Cell Transplantation, 2018, in press), suggesting immunorejection. Interestingly, phagocytosis of grafted hWJ-MSCs is reduced in the animals subjected to cyclosporine. In addition, we observed an increase of the glia cell line-derived neurotrophic factor (GDNF) expression in the host brain accompanies the hWJ-MSCs transplantation suggesting that the protective role of these cells is not associated to their survival but may be due to the secretion of trophic factors.


  hWJ-MSCs and Neuroprotection via Trophic Factor Secretion Top


Our observations suggest a neuroprotective function of hWJ-MSCs for the treatment of stroke. Notably, we showed that the transplantation of hWJ-MSCs significantly reduced IBA1 immunoreactivity and morphological activation of microglia in the peri-infarct area, but not in the core. In addition, in the core region, microglia displayed an amoeboid morphology indicating inflammatory response. Indeed, the CM-DiI fluorescence was found mainly in microglia in the core region suggesting phagocytosis of grafted cells. Similarly, the localization of MSCs was obtained from GFP-transgenic rats and double-labeled with 5-bromo-2-deoxyuridine (BrdU) and bis benzamide (BBZ) before the transplantation in rats.[17] The GFP signal was absent after 14 days of transplantation, while BrdU and BBZ markers were detected up to 12 weeks colocalized with host phagocytes, astrocytes, and neurons suggesting the immunorejection of the grafted cells.[17] In addition, a limited survival of neuronal-primed hMSCs has been reported by positive HuNuc staining detected only within 7 days in the host brain of hemiparkinsonian rats.[18] Interestingly, we detected an increased CM-DiI fluorescence, accompanied by a reduced phagocytosis of the grafted hWJ-MSCs with CsA treatment. These results support previous studies in which CsA treatment suppressed the endogenous microglia activation in oligodendrocyte progenitor cell transplantation.[19] Similarly, in an animal model of PD, CsA treatment improved the survival of human xenografts.[20] Therefore, CsA treatment may suppress immunorejection and increase the survival of hWJ-MSCs in transplants. On the other hand, studies on the neuroprotective effects of human cord blood cell transplantation have demonstrated functional improvements comparable to the results obtained without the CsA treatment in the present work.[21],[22],[23] Interestingly, these findings were associated with upregulation of the neurotrophic factor GDNF and no intravenous injected cell has been detected in the host brain after 3 days of transplantation in a rat model of stroke, even when co-infused with a blood–brain barrier (BBB) permeabilizer.[24] Therefore, considering that most of the grafted hWJ-MSCs were phagocytized by activated microglia, the improvement of neurological function observed in the absence of CsA treatment could be due to secretion of products able to cross the BBB. In concert with the findings of Borlongan et al., we also found a significantly increased GDNF expression in the host brain after hWJ-MSCs transplantation.[24] In addition, the same authors have previously reported a reduction in brain infarction and restored locomotory activity in a stroke animal model following treatment with GDNF protein or herpes simplex virus (HSV) amplicon-based vector encoding GDNF (HSV-GDNF).[25],[26] Similarly, the transplantation of GDNF containing cells, such as fetal kidney cells and reduced cerebral infarction in stroke animals.[27]


  Conclusion Top


In summary, these results suggest that the transplantation of hWJ-MSCs may be protective for the treatment of stroke, and this beneficial function does not necessarily require the survival of the grafted cells, but their secretion products.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
World Health Organization. The Top 10 Causes of Death; 2018. Available from: http://www.who.int/mediacentre/factsheets/fs310/en/index.html.  Back to cited text no. 1
    
2.
Watson N, Divers R, Kedar R, Mehindru A, Mehindru A, Borlongan MC, et al. Discarded Wharton Jelly of the human umbilical cord: A viable source for mesenchymal stromal cells. Cytotherapy 2015;17:18-24.  Back to cited text no. 2
    
3.
Donders R, Bogie JFJ, Ravanidis S, Gervois P, Vanheusden M, Marée R, et al. Human Wharton's Jelly-derived stem cells display a distinct immunomodulatory and proregenerative transcriptional signature compared to bone marrow-derived stem cells. Stem Cells Dev 2018;27:65-84.  Back to cited text no. 3
    
4.
Oppliger B, Joerger-Messerli MS, Simillion C, Mueller M, Surbek DV, Schoeberlein A, et al. Mesenchymal stromal cells from umbilical cord Wharton's Jelly trigger oligodendroglial differentiation in neural progenitor cells through cell-to-cell contact. Cytotherapy 2017;19:829-38.  Back to cited text no. 4
    
5.
Teixeira FG, Carvalho MM, Neves-Carvalho A, Panchalingam KM, Behie LA, Pinto L, et al. Secretome of mesenchymal progenitors from the umbilical cord acts as modulator of neural/glial proliferation and differentiation. Stem Cell Rev 2015;11:288-97.  Back to cited text no. 5
    
6.
Joerger-Messerli MS, Oppliger B, Spinelli M, Thomi G, di Salvo I, Schneider P, et al. Extracellular vesicles derived from Wharton's Jelly mesenchymal stem cells prevent and resolve programmed cell death mediated by perinatal hypoxia-ischemia in neuronal cells. Cell Transplant 2018;27:168-80.  Back to cited text no. 6
    
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Obtulowicz P, Lech W, Strojek L, Sarnowska A, Domanska-Janik K. Induction of endothelial phenotype from Wharton's Jelly-derived MSCs and comparison of their vasoprotective and neuroprotective potential with primary WJ-MSCs in CA1 hippocampal region ex vivo. Cell Transplant 2016;25:715-27.  Back to cited text no. 7
    
8.
Ding DC, Shyu WC, Chiang MF, Lin SZ, Chang YC, Wang HJ, et al. Enhancement of neuroplasticity through upregulation of beta1-integrin in human umbilical cord-derived stromal cell implanted stroke model. Neurobiol Dis 2007;27:339-53.  Back to cited text no. 8
    
9.
Fu YS, Cheng YC, Lin MY, Cheng H, Chu PM, Chou SC, et al. Conversion of human umbilical cord mesenchymal stem cells in Wharton's Jelly to dopaminergic neurons in vitro: Potential therapeutic application for parkinsonism. Stem Cells 2006;24:115-24.  Back to cited text no. 9
    
10.
Cheng T, Yang B, Li D, Ma S, Tian Y, Qu R, et al. Wharton's Jelly transplantation improves neurologic function in a rat model of traumatic brain injury. Cell Mol Neurobiol 2015;35:641-9.  Back to cited text no. 10
    
11.
Weiss ML, Medicetty S, Bledsoe AR, Rachakatla RS, Choi M, Merchav S, et al. Human umbilical cord matrix stem cells: Preliminary characterization and effect of transplantation in a rodent model of Parkinson's disease. Stem Cells 2006;24:781-92.  Back to cited text no. 11
    
12.
Huang PY, Shih YH, Tseng YJ, Ko TL, Fu YS, Lin YY, et al. Xenograft of human umbilical mesenchymal stem cells from Wharton's Jelly as a potential therapy for rat pilocarpine-induced epilepsy. Brain Behav Immun 2016;54:45-58.  Back to cited text no. 12
    
13.
Zhang L, Zhang HT, Hong SQ, Ma X, Jiang XD, Xu RX, et al. Cografted wharton's jelly cells-derived neurospheres and BDNF promote functional recovery after rat spinal cord transection. Neurochem Res 2009;34:2030-9.  Back to cited text no. 13
    
14.
Zhang X, Zhang Q, Li W, Nie D, Chen W, Xu C, et al. Therapeutic effect of human umbilical cord mesenchymal stem cells on neonatal rat hypoxic-ischemic encephalopathy. J Neurosci Res 2014;92:35-45.  Back to cited text no. 14
    
15.
Sabbaghziarani F, Mortezaee K, Akbari M, Kashani IR, Soleimani M, Moini A, et al. Retinoic acid-pretreated Wharton's Jelly mesenchymal stem cells in combination with triiodothyronine improve expression of neurotrophic factors in the subventricular zone of the rat ischemic brain injury. Metab Brain Dis 2017;32:185-93.  Back to cited text no. 15
    
16.
Zhang L, Wang LM, Chen WW, Ma Z, Han X, Liu CM, et al. Neural differentiation of human Wharton's Jelly-derived mesenchymal stem cells improves the recovery of neurological function after transplantation in ischemic stroke rats. Neural Regen Res 2017;12:1103-10.  Back to cited text no. 16
[PUBMED]  [Full text]  
17.
Coyne TM, Marcus AJ, Woodbury D, Black IB. Marrow stromal cells transplanted to the adult brain are rejected by an inflammatory response and transfer donor labels to host neurons and glia. Stem Cells 2006;24:2483-92.  Back to cited text no. 17
    
18.
Khoo ML, Tao H, Meedeniya AC, Mackay-Sim A, Ma DD. Transplantation of neuronal-primed human bone marrow mesenchymal stem cells in hemiparkinsonian rodents. PLoS One 2011;6:e19025.  Back to cited text no. 18
    
19.
Lü HZ, Wang YX, Zhou JS, Wang FC, Hu JG. Cyclosporin A increases recovery after spinal cord injury but does not improve myelination by oligodendrocyte progenitor cell transplantation. BMC Neurosci 2010;11:127.  Back to cited text no. 19
    
20.
Wang Y, Lin JC, Chiou AL, Liu JY, Liu JC, Zhou FC, et al. Human ventromesencephalic grafts restore dopamine release and clearance in hemiparkinsonian rats. Exp Neurol 1995;136:98-106.  Back to cited text no. 20
    
21.
Huang L, Liu Y, Lu J, Cerqueira B, Misra V, Duong TQ, et al. Intraarterial transplantation of human umbilical cord blood mononuclear cells in hyperacute stroke improves vascular function. Stem Cell Res Ther 2017;8:74.  Back to cited text no. 21
    
22.
Shahaduzzaman MD, Mehta V, Golden JE, Rowe DD, Green S, Tadinada R, et al. Human umbilical cord blood cells induce neuroprotective change in gene expression profile in neurons after ischemia through activation of akt pathway. Cell Transplant 2015;24:721-35.  Back to cited text no. 22
    
23.
Yan T, Venkat P, Chopp M, Zacharek A, Ning R, Cui Y, et al. Neurorestorative therapy of stroke in type 2 diabetes mellitus rats treated with human umbilical cord blood cells. Stroke 2015;46:2599-606.  Back to cited text no. 23
    
24.
Borlongan CV, Hadman M, Sanberg CD, Sanberg PR. Central nervous system entry of peripherally injected umbilical cord blood cells is not required for neuroprotection in stroke. Stroke 2004;35:2385-9.  Back to cited text no. 24
    
25.
Wang Y, Lin SZ, Chiou AL, Williams LR, Hoffer BJ. Glial cell line-derived neurotrophic factor protects against ischemia-induced injury in the cerebral cortex. J Neurosci 1997;17:4341-8.  Back to cited text no. 25
    
26.
Harvey BK, Chang CF, Chiang YH, Bowers WJ, Morales M, Hoffer BJ, et al. HSV amplicon delivery of glial cell line-derived neurotrophic factor is neuroprotective against ischemic injury. Exp Neurol 2003;183:47-55.  Back to cited text no. 26
    
27.
Chiang YH, Lin SZ, Borlongan CV, Hoffer BJ, Morales M, Wang Y, et al. Transplantation of fetal kidney tissue reduces cerebral infarction induced by middle cerebral artery ligation. J Cereb Blood Flow Metab 1999;19:1329-35.  Back to cited text no. 27
    



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Abstract
Introduction
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Functional Recov...
hWJ-MSCs and Neu...
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