Indonesia International (Bio)Medical Students Congress
2017
Intravenous delivery of bone marrow-derived
mesenchymal stem cells (BM-MSCs) enhances functional recovery and brain repair markers in ischemic stroke Afina Thara Pitaloka*, Ramadhanti Salma Ulwanda** and Nuzula Fikrin Nabila***
* Third Year Medical Student, Universitas Airlangga, (finapitaloka@gmail.com)
** Third Year Medical Student, Universitas Airlangga, (ulwanda@gmail.com)
*** Third Year Medical Student, Universitas Airlangga,
(fkrnnabila@gmail.com)
Correspondent author : Afina Thara Pitaloka (+628983887521, Faculty of
Medicine, Airlangga University, Mayjen Prof. Dr. Moestopo 47, Surabaya, finapitaloka@gmail.com)
Abstract
Stroke is a major contributor to the noncommunicable diseases worldwide. As one of
the neurodegenerative diseases, stroke causes loss of brain parenchyma and neurons, astrocytes, oligodendrocytes and endothelial cells. Ischemic strokes as one of the types of stroke account for about 80-85% of all strokes. Nowadays, there is a lack of effective treatment to promote tissue repair and functional recovery after the ischemic attack. Thus, strategies such as cell-based therapies with mesenchymal stem cells (MSCs) pave the way for new treatment options for stroke. Bone marrow- derived mesenchymal stem cells (BM-MSCs) therapy is one of the most promising methods to treat and promote recovery from ischemic stroke. This literature review aims to evaluate the therapeutic potential of BM-MSCs in ischemic stroke. Studies showed that intravenous administration of BM-MSCs significantly improved function and also increased the level of vascular endothelial growth factor (VEGF), synaptophysin, oligodendrocyte (Olig-2) and neurofilament. Furthermore, MSCs have many advantages. MSCs can be obtained, amplified, and stored for immediate use after stroke. MSCs also do not express Major histocompatibility complex II (MCH-II), so it could minimize the risk of rejection in patients.
Keywords: bone marrow; intravenous; ischemic stroke; mesenchymal stem cells.
Introduction types relevant to repair, modulate the immune system, promote neurogenesis, Stroke is a major contributor to the and secrete neuroprotective factors.1,3,4 global non-communicable diseases. Another research also suggests that the About 15 million people suffer from reduction of inflammatory component stroke, with approximately six millions complement 3 (C3) expression by of deaths annually. In the US, 87% MSCs can help to alleviate ischemic strokes account as ischemic stroke. brain damage, and can be used for a Combining the expectation that the new neuroprotective strategy in stroke number of people over the age of 65 therapy.4,5 will double by 2030, and that the risk of suffering a stroke doubles for each This literature review aims to discuss decade over the age of 55, will even the usage of BM-MSCs given lead to a further increase in patient intravenously for the treatment of numbers with permanent disabilities ischemic stroke. and socioeconomic burden.1 Stroke causes loss of brain parenchyma and Materials and Methods neurons, astrocytes, oligodendrocytes and endothelial cells.2,3 We have done a systematic literature search for relevant clinical researches Ischemic stroke is most frequently and reviews published between 2008 caused by thromboembolisms while and 2017 using Pubmed, ScienceDirect hemorrhagic stroke most often results and Google Scholar. The search from vessel wall pathology associated strategy consisted of MeSH (medical with hypertension and subject heading) words and keywords microaneurysms. This review will only related to the disease. Search words focus on ischemic stroke as the main were 'bone marrow', 'intravenous' or pathology. The specific therapies 'iv', 'ischemic stroke', and currently used for ischemic stroke 'mesenchymal stem cells'. All studies management are intervention to prevent about bone marrow mesenchymal stem inappropriate coagulation, surgical cells were included. We excluded procedures to repair vascular publications which were not in English. abnormalities, and thrombolytic therapy.2,4 Despite the high burden of Result and Discussion stroke, there is still a lack of effective treatment to promote tissue repair and Many studies, from preclinical to functional recovery after the ischemic clinical, have evaluated the potency of attack.2,3 BM-MSCs in many degenerative brain diseases, including ischemic stroke. Stem cell therapy is one of the most BM-MSCs contribute to the formation promising methods to treat and of hematopoietic stem cells niche that promote recovery from ischemic supports hematopoiesis. Within the stroke. Many studies regarding the bone marrow, MSCs can be isolated treatment of ischemic stroke have been from other BM cells due to their using bone marrow-derived potency to adhere to tissue culture mesenchymal stem cells (BM-MSCs). plastic. These cells have a spindle- BM-MSCs are promising therapy after shaped fibroblast-like morphology and ischemic stroke because of their can be expanded and enriched by advantageous characteristic, such as culturing for 3 to 5 weeks.3,6,7 their ability to differentiate into cell A study evaluated the effect of response to repair processes, and this intravenously administered BM-MSCs could amplify trophic factor levels in (2 106 cells) 30 minutes after the brain. A study found that BM- permanent middle cerebral artery MSCs increased cellular proliferation occlusion (pMCAO) to rats as the and modified brain repair markers model of ischemic stroke at 24 hours levels.1,7,8 and 14 days. It showed that BM-MSCs therapy reduced the number of Vascular endothelial growth factor TUNEL+ cells in the peri-infarct area (VEGF) levels were significantly which means decreased cell death. higher in the rat brain after BM-MSCs According to this study, at 14 days, the therapy compared with the control untreated group showed significantly group by 4.84 (A.U.) and 2.75 (A.U.) more TUNEL+ cells than the BM- respectively. The levels of Olig-2 MSCs group, with number of labeling were also considerably higher TUNEL+ cells 41 6.4 and 26 5.5 than in the control group after the BM- respectively.1,7,8 MSCs treatment with the number 2.05 (A.U.) and 2.89 (A.U.) respectively.1,7 BM-MSCs also increased cellular proliferation after pMCAO. Recovery after stroke is a dynamic Quantitative analysis showed that the process, and the growth and trophic infarct group displayed a significantly factors produced by BM-MSCs may smaller decrease in the peri-infarct affect synaptogenesis in the ischemic zone at 14 days after focal cerebral brain. Compared with the control ischemia than did the BM-MSCs.1,7 group, synaptophysin (SYP) levels were also significantly increased after A study demonstrated that infarct size BM-MSCs administration with the measured by MRI in rats with pMCAO number 2.15 (A.U.) and 3.14 (A.U.) does not change after administration of respectively. Lastly, neurofilament (NF) intravenous BM-MSCs, but some levels were significantly increased previous studies showed a decrease.1,7,8 after the BM-MSCs treatment compared with the control group by The study also revealed that the BM- 2.10 (A.U.) and 1.18 (A.U.) MSCs treated groups showed good respectively. The BDNF levels were functional recovery at 24 hours and 14 also higher after BM-MSCs therapy, days compared with the untreated but this increase did not reach infarct group (Figure 1).1 statistical significance. The GFAP levels were decreased significantly This result is in line with other studies after BM-MSCs administration in which also showed that administration comparison with the infarct group.1,7,8 of BM-MSCs in animal models improved sensorimotor function. In ischemic stroke, BM-MSCs Another study also found that BM- establishes neuronal protection through MSCs enhanced synaptogenesis and inflammatory and immune response nerve regeneration, while decreased modulation. BM-MSCs has been tissue plasminogen activator (tPA)- shown to upregulate interleukin-6 (IL- induced brain damage.6,9 6) expression in a mouse model, which probably accounts for neuroprotective Studies found that BM-MSCs secrete a effect. Soluble factors secreted from wide array of neurotrophins, growth BM-MSCs, such as IL-6, IL-8, factors, cytokines and other soluble chemokine ligand 2 (CCL2), VEGF, factors such as VEGF or BDNF, in hepatocyte growth factor, and bone by modified Rankin scale (mRS) morphogenetic protein-4 (BMP-4) also (Figure 2). This clinical improvement increase maturation and survival of is believed to be associated with serum neuron. The same research also levels of stromal cell-derived factor- suggests that neuroprotective effect of 1.12 MSCs in cerebral ischemia is associated with the down-regulation of Conclusion C3 expression.5,7 The use of BM-MSCs intravenously as In particular, intravenously injected a therapy after an ischemic attack can BM-MSCs enter the brain and reduce ischemic damage, significantly stimulate local production of growth improved functional recovery, and factors from endogenous cells like increase brain repair markers. Its astrocytes and endothelial cells. These effects on the ischemic tissues can also growth factors lead to angiogenesis promote angiogenesis and and vascular stabilization. Intravenous synaptogenesis through the increase of administration of BM-MSCs leads to a VEGF, SYP, Olig-2 and NF levels. time-dependent release of Neuroprotective effects are achieved neurotrophins and angiogenic growth through the modulation of factors. The production of these inflammatory and immune response. molecules all contributes to and likely MSCs is also advantageous for their coordinates the improvement in obtainability and can be easily neurological function post stroke.1,7,8 amplified and stored for immediate use when needed after an attack. They also The use of BM-MSCs for therapies are have minimal risk of rejection because advantageous because they are easy to of the unexpressed MCH-II. harvest, can be quickly isolated, expanded and stored for a period, can Further studies are necessary to explain be administered in various ways, are the beneficial effects, efficacy, and relatively immune-privileged, and they safety related to MSCs therapy, may be administered through different especially in the human model. But, methods.9,10,11 the intravenous MSCs therapy remains as one of the most promising methods Furthermore, it is known that BM- to treat and promote recovery from MSCs do not express major ischemic stroke. histocompatibility complex II (MCH- II), thus minimizing the risk of Acknowledgement rejection in patients and facilitates their allogeneic administration. It possibly We would like to acknowledge the allows BM-MSCs from healthy donors support and guidance from all to be stored in biobanks for the mentoring lecturers. treatment of stroke patients during the acute phase of the disease.7,9,10 Conflict of Interest
Clinical trials in ischemic stroke The authors declare that there is no
patients showed that administration of conflict of interest in this work. intravenous BM-MSCs is safe and no significant side effects were observed References during the treatment.11,12 A study also found that BM-MSCs therapy improves clinical outcome measured 1. Gutirrez-Fernndez M, 7. Liu X, Ye R, Yan T, et al. Cell Rodrguez-Frutos B, Ramos- based therapies for ischemic Cejudo J, et al. Effects of stroke: From basic science to intravenous administration of bedside. Progress in allogenic bone marrow- and Neurobiology. 2014;115:92-115. adipose tissue-derived 8. Bang O. Clinical Trials of Adult mesenchymal stem cells on Stem Cell Therapy in Patients functional recovery and brain with Ischemic Stroke. Journal of repair markers in experimental Clinical Neurology. ischemic stroke. Stem Cell 2016;12(1):14. Research & Therapy. 9. Bang O. Clinical Trials of Adult 2013;4(1):11. Stem Cell Therapy in Patients 2. Jeong C, Kim S, Lim J, et al. with Ischemic Stroke. 2017. Mesenchymal Stem Cells 10. Tanna T, Sachan V. Expressing Brain-Derived Mesenchymal Stem Cells: Neurotrophic Factor Enhance Potential in Treatment of Endogenous Neurogenesis in an Neurodegenerative Diseases. Ischemic Stroke Model. BioMed Current Stem Cell Research & Research International. Therapy. 2014;9(6):513-521. 2014;2014:1-10. 11. Friedrich M. Intra-Arterial 3. Dulamea A. The potential use of Infusion of Autologous Bone- mesenchymal stem cells in stroke Marrow Mononuclear Cells in therapyFrom bench to bedside. Patients with Moderate to Severe Journal of the Neurological Middle-Cerebral-Artery Acute Sciences. 2015;352(1-2):1-11. Ischemic Stroke. Cell 4. Gervois P, Wolfs E, Ratajczak J, Transplantation. 2012. et al. Stem Cell-Based Therapies 12. Lee J, Hong J, Moon G, et al. A for Ischemic Stroke: Preclinical Long-Term Follow-Up Study of Results and the Potential of Intravenous Autologous Imaging-Assisted Evaluation of Mesenchymal Stem Cell Donor Cell Fate and Mechanisms Transplantation in Patients With of Brain Regeneration. Medicinal Ischemic Stroke. STEM CELLS. Research Reviews. 2010;28(6):1099-1106. 2016;36(6):1080-1126. 5. Jung H, Jeong S, Yang J, et al. Neuroprotective effect of mesenchymal stem cell through complement component 3 downregulation after transient focal cerebral ischemia in mice. Neuroscience Letters. 2016;633:227-234. 6. Huang W, Mo X, Qin C, Zheng J, Liang Z, Zhang C. Transplantation of differentiated bone marrow stromal cells promotes motor functional recovery in rats with stroke. Neurological Research. 2013;35(3):320-328. Long-Term Follow-Up Study of Intravenous Autologous Appendixes Mesenchymal Stem Cell Transplantation in Patients With Ischemic Stroke. STEM CELLS. 2010;28(6):1099-1106.)
Fig. 1. Acute intravenous (i.v.)
administration of bone marrow-derived mesenchymal (BM-MSC) cells improved functional recovery at 24 h and 14 d after permanent middle cerebral artery occlusion (pMCAO). 1 (Gutirrez-Fernndez M, Rodrguez-Frutos B, Ramos- Cejudo J, Teresa Vallejo-Cremades M, Fuentes B, Cerdn S et al. Effects of intravenous administration of allogenic bone marrow- and adipose tissue-derived mesenchymal stem cells on functional recovery and brain repair markers in experimental ischemic stroke. Stem Cell Research & Therapy. 2013;4(1):11.)
Fig. 2. Proportion of patients in the
control and MSC group according to the mRS at day 7 of admission and last evaluation. 12 (Lee J, Hong J, Moon G, et al. A
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