Mesenchymal stem cells  stroke
214630643
Activated Mesenchymal Stem Cells Induce Recovery Following Stroke Via Regulation of Inflammation and Oligodendrogenesis
Background Brain repair mechanisms fail to promote recovery after stroke, and approaches to induce brain regeneration are scarce. Mesenchymal stem cells (MSC) are thought to be a promising therapeutic option. However, their efficacy is not fully elucidated, and the mechanism underlying their effect is not known. Methods and Results The middle cerebral artery occlusion model was utilized to determine the efficacy of interferon g activated mesenchymal stem cells (aMSCg) as an acute therapy for stroke. Here we show that treatment with aMSCg is a more potent therapy for stroke than naive MSC. aMSCg treatment results in significant functional recovery assessed by the modified neurological severity score and open field analysis compared with vehicle treated animals. aMSCg treated animals showed significant reductions in infarct size and inhibition of microglial activation. The aMSCg treatment suppressed the hypoxia induced microglial proinflammatory phenotype more effectively than treatment with naive MSC. Importantly, treatment with aMSCg induced recruitment and differentiation of oligodendrocyte progenitor cells to myelin producing oligodendrocytes in vivo. To elucidate the mechanism underlying high efficacy of aMSCg therapy, we examined the secretome of aMSCg and compared it to that of naive MSC. Intriguingly, we found that aMSCg but not nMSC upregulated neuron glia antigen 2, an important extracellular signal and a hallmark protein of oligodendrocyte progenitor cells. Conclusions These results suggest that activation of MSC with interferon g induces a potent proregenerative, promyelinating, and anti inflammatory phenotype of these cells, which increases the potency of aMSCg as an effective therapy for ischemic stroke.
Journal of the American Heart Association
Matthew K Tobin Terilyn Koehler Lawson Stephen Kyra L Lopez Melissa R Pergande Amelia Bartholomew Stephanie M Cologna Orly Lazarov
218898840
Autologous Mesenchymal Stem Cells Improve Motor Recovery in Subacute Ischemic Stroke: a Randomized Clinical Trial
While preclinical stroke studies have shown that mesenchymal stem cells (MSCs) promote recovery, few randomized controlled trials (RCT) have assessed cell therapy in humans. In this RCT, we assessed the safety, feasibility, and efficacy of intravenous autologous bone marrow derived MSCs in subacute stroke. ISIS HERMES was a single center, open label RCT, with a 2 year follow up. We enrolled patients aged 18 70 years less than 2 weeks following moderate severe ischemic carotid stroke. Patients were randomized 2:1 to receive intravenous MSCs or not. Primary outcomes assessed feasibility and safety. Secondary outcomes assessed global and motor recovery. Passive wrist movement functional MRI (fMRI) activity in primary motor cortex (MI) was employed as a motor recovery biomarker. We compared "treated" and "control" groups using as treated analyses. Of 31 enrolled patients, 16 patients received MSCs. Treatment feasibility was 80% and there were 10 and 16 adverse events in treated patients, and 12 and 24 in controls at 6 month and 2 year follow up, respectively. Using mixed modeling analyses, we observed no treatment effects on the Barthel Index, NIHSS, and modified Rankin scores, but significant improvements in motor NIHSS p 0.004) motor Fugl Meyer scores p 0.028) and task related fMRI activity in MI 4a p 0.031) and MI 4p p 0.002) Intravenous autologous MSC treatment following stroke was safe and feasible. Motor performance and task related MI activity results suggest that MSCs improve motor recovery through sensorimotor neuroplasticity. ClinicalTrials.gov Identifier NCT 00875654
Translational Stroke Research
Assia Jaillard Marc Hommel Anaick Moisan Thomas A Zeffiro Isabelle M Favre-Wiki Marianne Barbieux-Guillot Wilfried Vadot Sebastien Marcel Laurent Lamalle Sylvie Grand Olivier Detante
202565238
Neuroinflammation as a target for treatment of stroke using mesenchymal stem cells and extracellular vesicles
Ischemic stroke is the third cause of death in the developed countries and the main reason of severe disability. Brain ischemia leads to the production of damage associated molecular patterns (DAMPs) by neurons and glial cells which results in astrocyte and microglia activation, pro inflammatory cytokines and chemokines production, blood brain barrier (BBB) disruption, infiltration of leukocytes from the peripheral blood into the infarcted area, and further exacerbation of tissue damage. However, some immune cells such as microglia or monocytes are capable to change their phenotype to anti inflammatory, produce anti inflammatory cytokines, and protect injured nervous tissue. In this situation, therapies, which will modulate the immune response after brain ischemia, such as transplantation of mesenchymal stem cells (MSCs) are catching interest. Many experimental studies of ischemic stroke revealed that MSCs are able to modulate immune response and act neuroprotective, through stimulation of neurogenesis, oligodendrogenesis, astrogenesis, and angiogenesis. MSCs may also have an ability to replace injured cells, but the release of paracrine factors directly into the environment or via extracellular vesicles (EVs) seems to play the most pronounced role. EVs are membrane structures containing proteins, lipids, and nucleic acids, and they express similar properties as the cells from which they are derived. However, EVs have lower immunogenicity, do not express the risk of vessel blockage, and have the capacity to cross the blood brain barrier. Experimental studies of ischemic stroke showed that EVs have immunomodulatory and neuroprotective properties; therefore, they can stimulate neurogenesis and angiogenesis. Up to now, 20 clinical trials with MSC transplantation into patients after stroke were performed, from which two concerned on only hemorrhagic stroke and 13 studied only on ischemic stroke. There is no clinical trial with EV injection into patients after brain ischemia so far, but the case with miR 124 enriched EVs administration is planned and probably there will be more clinical studies with EV transplantation in the near future.
Journal of Neuroinflammation
Sylwia Dabrowska Anna Katarzyna Andrzejewska Barbara Lukomska Miroslaw Janowski
210870286
Systemic conditioned medium treatment from interleukin 1 primed mesenchymal stem cells promotes recovery after stroke
Background Mesenchymal stem cells (MSCs) hold great potential as a therapy for stroke and have previously been shown to promote recovery in preclinical models of cerebral ischaemia. MSCs secrete a wide range of growth factors, chemokines, cytokines and extracellular vesicles collectively termed the secretome. In this study, we assessed for the first time the efficacy of the IL 1a primed MSC derived secretome on brain injury and functional recovery after cerebral ischaemia. Methods Stroke was induced in male C57BL/6 mice using the intraluminal filament model of middle cerebral artery occlusion. Conditioned medium from IL 1a primed MSCs or vehicle was administered at the time of reperfusion or at 24 h post stroke by subcutaneous injection. Results IL 1a primed MSC derived conditioned medium treatment at the time of stroke led to a 30% reduction in lesion volume at 48 h and was associated with modest improvements in body mass gain, 28 point neurological score and nest building. Administration of MSC derived conditioned medium at 24 h post stroke led to improved nest building and neurological score despite no observed differences in lesion volume at day 2 post stroke. Conclusions Our results show for the first time that the administration of conditioned medium from IL 1a primed MSCs leads to improvements in behavioural outcomes independently of neuroprotection.
Stem cell research therapy
Catriona J Cunningham Raymond Wong Jack Barrington Sabrina Tamburrano Emmanuel Pinteaux Stuart M Allan
201983311
Phase I/II Study of Safety and Preliminary Efficacy of Intravenous Allogeneic Mesenchymal Stem Cells in Chronic Stroke.
Background and Purpose Stroke is a leading cause of long term disability. Limited treatment options exist for patients with chronic stroke and substantial functional deficits. The current study examined safety and preliminary efficacy estimates of intravenous allogeneic mesenchymal stem cells in this population. Methods Entry criteria included ischemic stroke >6 months prior and substantial impairment (National Institutes of Health Stroke Scale score =6) and disability. Enrollees received a single intravenous dose of allogeneic ischemia tolerant mesenchymal stem cells. Phase 1 used a dose escalation design (3 tiers, n=5 each) Phase 2 was an expanded safety cohort. The primary end point was safety over 1 year. Secondary end points examined behavioral change. Results In phase 1 (n=15) each dose (0.5, 1.0, and 1.5 million cells/kg body weight) was found safe, so phase 2 subjects (n=21) received 1.5 million cells/kg. At baseline, subjects (n=36) averaged 4.2+ 4.6 years poststroke, age 61.1+ 10.8 years, National Institutes of Health Stroke Scale score 8 (6.5 10) and Barthel Index 65+ 29. Two were lost to follow up, one was withdrawn and 2 died (unrelated to study treatment) Of 15 serious adverse events, none was possibly or probably related to study treatment. Two mild adverse events were possibly related to study treatment, a urinary tract infection and intravenous site irritation. Treatment was safe based on serial exams, electrocardiograms, laboratory tests, and computed tomography scans of chest/abdomen/pelvis. All behavioral end points showed significant gains over the 12 months of follow up. For example, Barthel Index scores increased by 6.8+ 11.4 points (mean+ SD) at 6 months (P=0.002) and by 10.8+ 15.5 points at 12 months (P<0.001) post infusion; the proportion of patients achieving excellent functional outcome (Barthel score =95) increased from 11.4% at baseline to 27.3% at 6 months and to 35.5% at 12 months. Conclusions Intravenous transfusion of allogeneic ischemia tolerant mesenchymal stem cell in patients with chronic stroke and substantial functional deficits was safe and suggested behavioral gains. These data support proceeding to a randomized, placebo controlled study of this therapy in this population. Clinical Trial Registration URL: http:/www.clinicaltrials.gov. Unique identifier: NCT01297413.
Stroke
Michael L Levy John R Crawford Nabil Dib Lev Verkh Nikolai I Tankovich Steven C Cramer
210831377
Early Transplantation of Human Cranial Bone derived Mesenchymal Stem Cells Enhances Functional Recovery in Ischemic Stroke Model Rats
We analyzed the cell characteristics, neuroprotective, and transplantation effects of human cranial bone derived mesenchymal stem cells (hcMSCs) in ischemic stroke model rats compared with human iliac bone derived mesenchymal stem cells (hiMSCs) The expressions of brain derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) as neurotrophic factors were analyzed in both MSCs. hiMSCs or hcMSCs were intravenously administered into ischemic stroke model rats at 3 or 24 h after middle cerebral artery occlusion (MCAO) and neurological function was evaluated. The survival rate of neuroblastoma x glioma hybrid cells (NG108 15) after 3 or 24 h oxidative or inflammatory stress and the neuroprotective effects of hiMSCs or hcMSCs conditioned medium (CM) on 3 or 24 h oxidative or inflammatory stress exposed NG108 15 cells were analyzed. The expressions of BDNF and VEGF were higher in hcMSCs than in hiMSCs. hcMSCs transplantation at 3 h after MCAO resulted in significant functional recovery compared with that in the hiMSCs or control group. The survival rate of stress exposed NG108 15 was lower after 24 h stress than after 3 h stress. The survival rates of NG108 15 cells cultured with hcMSCs CM after 3 h oxidative or inflammatory stress were significantly higher than in the control group. Our results suggest that hcMSCs transplantation in the early stage of ischemic stroke suppresses the damage of residual nerve cells and leads to functional recovery through the strong expressions of neurotrophic factors. This is the first report demonstrating a functional recovery effect after ischemic stroke following hcMSCs transplantation.
Neurologia medico chirurgica
Jumpei Oshita T Okazaki Takafumi Mitsuhara Takeshi Imura Kei Nakagawa Takashi Otsuka Tomoyuki Kurose Takayuki Tamura Masaru Abiko Masaaki Takeda Yumi Kawahara Louis Yuge Kaoru Kurisu
225057066
Enhancing the Therapeutic Potential of CCL2 Overexpressing Mesenchymal Stem Cells in Acute Stroke
Although intravenous administration of mesenchymal stem cells (MSCs) is effective for experimental stroke, low engraftment and the limited functional capacity of transplanted cells are critical hurdles for clinical applications. C C motif chemokine ligand 2 (CCL2) is associated with neurological repair after stroke and delivery of various cells into the brain via CCL2/CCR2 (CCL2 receptor) interaction. In this study, after CCL2 overexpressing human umbilical cord derived MSCs (hUC MSCs) were intravenously transplanted with mannitol in rats with middle cerebral arterial occlusion, we compared the differences between four different treatment groups: mannitol CCL2 overexpressing hUC MSCs (CCL2 MSC) mannitol naive hUC MSCs (M MSC) mannitol only, and control. At four weeks post transplantation, the CCL2 MSC group showed significantly better functional recovery and smaller stroke volume relative to the other groups. Additionally, we observed upregulated levels of CCR2 in acute ischemic brain and the increase of migrated stem cells into these areas in the CCL2 MSC group relative to the M MSC. Moreover, the CCL2 MSC group displayed increased angiogenesis and endogenous neurogenesis, decreased neuro inflammation but with increased healing process inflammatory cells relative to other groups. These findings indicated that CCL2 overexpressing hUC MSCs showed better functional recovery relative to naive hUC MSCs according to the increased migration of these cells into brain areas of higher CCR2 expression, thereby promoting subsequent endogenous brain repair.
International journal of molecular sciences
Sang-Hun Lee Ok Joon Kim Kee-Ook Lee Hye-ju Jung Seung-hun Oh Nam Keun Kim
218906946
VX 765 enhances autophagy of human umbilical cord mesenchymal stem cells against stroke induced apoptosis and inflammatory responses via AMPK/mTOR signaling pathway
To investigate the protective effect of VX 765 on human umbilical mesenchymal stem cells (HUMSCs) in stroke and its mechanism.
CNS neuroscience therapeutics
Zhezhe Sun Lei Gu Ke Wu Kankai Wang Junnan Ru Su Yang Zhenzhong Wang Qichuan Zhuge Lijie Huang Shengwei Huang
220890612
The conditioned medium of human embryonic stem cell derived mesenchymal stem cells alleviates neurological deficits and improves synaptic recovery in experimental stroke
The transplantation of mesenchymal stem cells (MSCs) is of main approaches in regenerative therapy for stroke. Due to the potential tumorigenicity and low survival rate of transplanted cells, focuses have been shifted from cell replacement to their paracrine effects. Therefore, stem cell conditioned medium (CM) therapy has emerged as an alternative candidate. Here, we investigated the effect of CM derived from human embryonic MSCs on experimental ischemic stroke. Wistar rats underwent ischemic stroke by the right middle cerebral artery occlusion (MCAO) CM was infused either one time (1 hr post MCAO) or three times (1, 24, and 48 hr post MCAO) through guide cannula into the left lateral ventricle. Neurological functions were evaluated using Bederson's test and modified Neurological Severity Score on Days 1, 3, and 7 following MCAO. Infarction volumes and cerebral edema were measured on Days 3 and 7. growth associated protein 43, synaptophysin, cAMP response element binding protein, and phosphorylated cAMP response element binding protein levels were also assessed in peri ischemic cortical tissue on Day 7 postsurgery. Our results indicated that three times injections of CM could significantly reduce body weight loss, mortality rate, infarct volumes, cerebral edema, and improve neurological deficits in MCAO rats. Moreover, three injections of CM could restore decreased levels of synaptic markers in MCAO rats up to its normal levels observed in the sham group. Our data suggest that using the CM obtained from embryonic stem cells MSCs could be a potent therapeutic approach to attenuate cerebral ischemia insults which may be partly mediated through modulation of synaptic plasticity.
Journal of cellular physiology
Afsaneh Asgari Taei Leila Dargahi Sanaz Nasoohi Gholamreza Hassanzadeh Mehdi Kadivar Maryam Farahmandfar
228067105
Adipose derived mesenchymal stem cells reduce autophagy in stroke mice by extracellular vesicle transfer of miR 25
Abstract Grafted mesenchymal stem cells (MSCs) yield neuroprotection in preclinical stroke models by secreting extracellular vesicles (EVs) The neuroprotective cargo of EVs, however, has not yet been identified. To investigate such cargo and its underlying mechanism, primary neurons were exposed to oxygen glucose deprivation (OGD) and cocultured with adipose derived MSCs (ADMSCs) or ADMSC secreted EVs. Under such conditions, both ADMSCs and ADMSC secreted EVs significantly reduced neuronal death. Screening for signalling cascades being involved in the interaction between ADMSCs and neurons revealed a decreased autophagic flux as well as a declined p53 BNIP3 activity in neurons receiving either treatment paradigm. However, the aforementioned effects were reversed when ADMSCs were pretreated with the inhibitor of exosomal secretion GW4869 or when Hrs was knocked down. In light of miR 25 3p being the most highly expressed miRNA in ADMSC EVs interacting with the p53 pathway, further in vitro work focused on this pathway. Indeed, a miR 25 3p oligonucleotide mimic reduced cell death, whereas the anti oligonucleotide increased autophagic flux and cell death by modulating p53 BNIP3 signalling in primary neurons exposed to OGD. Likewise, native ADMSC EVs but not EVs obtained from ADMSCs pretreated with the anti miR 25 3p oligonucleotide (ADMSC EVsanti miR 25 3p) confirmed the aforementioned in vitro observations in C57BL/6 mice exposed to cerebral ischemia. The infarct size was reduced, and neurological recovery was increased in mice treated with native ADMSC EVs when compared to ADMSC EVsanti miR 25 3p. ADMSCs induce neuroprotection by improved autophagic flux through secreted EVs containing miR 25 3p. Hence, our work uncovers a novel key factor in naturally secreted ADMSC EVs for the regulation of autophagy and induction of neuroprotection in a preclinical stroke model.
Journal of extracellular vesicles
Yaoyun Kuang Xuan Zheng Lin Zhang Xiaoyu Ai Vivek Venkataramani Ertugrul Kilic Dirk M Hermann Arshad Abdul Majid Mathias Bahr Thorsten R Doeppner