We previously evaluated the short-term follow-up preliminary data of mesenchymal stem cells (MSCs) transplantation in patients with ischemic stroke. The present study was conducted to evaluate the long-term safety and efficacy of i.v. MSCs transplantation in a larger population. To accomplish this, we performed an open-label, observer-blinded clinical trial of 85 patients with severe middle cerebral artery territory infarct. Patients were randomly allocated to one of two groups, those who received i.v. autologous ex vivo cultured MSCs (MSC group) or those who did not (control group), and followed for up to 5 years. Mortality of any cause, long-term side effects, and new-onset comorbidities were monitored. Of the 52 patients who were finally included in this study, 16 were the MSC group and 36 were the control group. Four (25%) patients in the MSC group and 21 (58.3%) in the control group died during the follow-up period, and the cumulative surviving portion at 260 weeks was 0.72 in the MSC group and 0.34 in the control group (log-rank; p = .058). Significant side effects were not observed following MSC treatment. The occurrence of comorbidities including seizures and recurrent vascular episodes did not differ between groups. When compared with the control group, the follow-up modified Rankin Scale (mRS) score was decreased, whereas the number of patients with a mRS of 0-3 increased in the MSC group (p = .046). Clinical improvement in the MSC group was associated with serum levels of stromal cell-derived factor-1 and the degree of involvement of the subventricular region of the lateral ventricle. Intravenous autologous MSCs transplantation was safe for stroke patients during long-term follow-up. This therapy may improve recovery after stroke depending on the specific characteristics of the patients.

https://stemcellsjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/stem.430

A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke.

Mesenchymal stem cells: Mechanisms of immunomodulation and homing.

The past decade has seen an explosion of research directed toward better understanding of the mechanisms of mesenchymal stem/stromal cell (MSC) function during rescue and repair of injured organs and tissues. In addition to delineating cell–cell signaling and molecular controls for MSC differentiation, the field has made particular progress in defining several other mechanisms through which administered MSCs can promote tissue rescue/repair. These include: 1) paracrine activity that involves secretion of proteins/peptides and hormones; 2) transfer of mitochondria by way of tunneling nanotubes or microvesicles; and 3) transfer of exosomes or microvesicles containing RNA and other molecules. Improved understanding of MSC function holds great promise for the application of cell therapy and also for the development of powerful cell-derived therapeutics for regenerative medicine. Focusing on these three mechanisms, we discuss MSC-mediated effects on immune cell responses, cell survival, and fibrosis and review recent progress with MSC-based or MSC-derived therapeutics.

/pdf/mechanisms-of-mesenchymal-stem-stromal-cell-function-3tveuuxtt1.pdf

Mechanisms of mesenchymal stem/stromal cell function

Summary Restorative cell-based and pharmacological therapies for experimental stroke substantially improve functional outcome. These therapies target several types of parenchymal cells (including neural stem cells, cerebral endothelial cells, astrocytes, oligodendrocytes, and neurons), leading to enhancement of endogenous neurogenesis, angiogenesis, axonal sprouting, and synaptogenesis in the ischaemic brain. Interaction between these restorative events probably underpins the improvement in functional outcome. This Review provides examples of cell-based and pharmacological restorative treatments for stroke that stimulate brain plasticity and functional recovery. The molecular pathways activated by these therapies, which induce remodelling of the injured brain via angiogenesis, neurogenesis, and axonal and dendritic plasticity, are discussed. The ease of treating intact brain tissue to stimulate functional benefit in restorative therapy compared with treating injured brain tissue in neuroprotective therapy might more readily help with translation of restorative therapy from the laboratory to the clinic.

/pdf/neurorestorative-therapies-for-stroke-underlying-mechanisms-2d8ugztdrv.pdf

Neurorestorative therapies for stroke: underlying mechanisms and translation to the clinic

As part of the neurovascular unit, the blood-brain barrier (BBB) is a unique, dynamic regulatory boundary that limits and regulates the exchange of molecules, ions, and cells between the blood and ...

Neuroinflammatory mechanisms of blood-brain barrier damage in ischemic stroke.

SDF-1α/CXCR4-mediated migration of systemically transplanted bone marrow stromal cells towards ischemic brain lesion in a rat model

Background: Transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) could ameliorate neurological deficits after stroke in the rodent. Objective: The purpose of this study was to investigate the potential mechanisms underlying the neuroprotective effects of implanted BMSCs. Methods: Ischemic stroke was induced by permanent middle cerebral artery occlusion (MCAo) in Sprague-Dawley rats. BMSCs were intravenously transplanted at 24 hours after MCAo. Neurological function was evaluated using modified neurological severity score and Morris water maze test. Immunohistochemistry and terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling staining were performed to detect neuronal apoptosis and proliferation. The protein and mRNA levels of vascular endothelial growth factor (VEGF) were determined by ELISA and reverse transcriptase polymerase chain reaction, respectively. Results: Significant improvement of neurological deficits was found in BMSC-treated rats compared with contr...

Guang-Qian Zhou

Papers

SDF-1α/CXCR4-mediated migration of systemically transplanted bone marrow stromal cells towards ischemic brain lesion in a rat model

Intravenously administered BMSCs reduce neuronal apoptosis and promote neuronal proliferation through the release of VEGF after stroke in rats.