Mesenchymal Stromal Cells in Stroke: Improvement of Motor Recovery or Functional Compensation?

Boltze, Johannes; Łukomska, Barbara; Jolkkonen, Jukka; consortium, MEMS-IRBI

doi:10.1038/jcbfm.2014.94

Cited by 51 publications

(31 citation statements)

References 10 publications

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“…Next we investigated whether EC-targeted HSP27 overexpression leads to long-term functional improvements in stroke mice. Commonly used neurobehavioral tests for assessing neurological deficits of mice show different patterns and time course of spontaneous recovery in stroke animals (23)(24)(25). To comprehensively evaluate sensorimotor functions after stroke, a battery of four different behavioral tests was performed on WT, N-HSP27, and EC-HSP27 mice before and up to 21 d after tFCI ( Fig.…”

Section: Ec-specific Overexpression Of Hsp27 Ameliorates Bbb Disruptionmentioning

confidence: 99%

Endothelium-targeted overexpression of heat shock protein 27 ameliorates blood–brain barrier disruption after ischemic brain injury

Shi

Jiang

Zhang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

118

144

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The damage borne by the endothelial cells (ECs) forming the blood–brain barrier (BBB) during ischemic stroke and other neurological conditions disrupts the structure and function of the neurovascular unit and contributes to poor patient outcomes. We recently reported that structural aberrations in brain microvascular ECs—namely, uncontrolled actin polymerization and subsequent disassembly of junctional proteins, are a possible cause of the early onset BBB breach that arises within 30–60 min of reperfusion after transient focal ischemia. Here, we investigated the role of heat shock protein 27 (HSP27) as a direct inhibitor of actin polymerization and protectant against BBB disruption after ischemia/reperfusion (I/R). Using in vivo and in vitro models, we found that targeted overexpression of HSP27 specifically within ECs—but not within neurons—ameliorated BBB impairment 1–24 h after I/R. Mechanistically, HSP27 suppressed I/R-induced aberrant actin polymerization, stress fiber formation, and junctional protein translocation in brain microvascular ECs, independent of its protective actions against cell death. By preserving BBB integrity after I/R, EC-targeted HSP27 overexpression attenuated the infiltration of potentially destructive neutrophils and macrophages into brain parenchyma, thereby improving long-term stroke outcome. Notably, early poststroke administration of HSP27 attached to a cell-penetrating transduction domain (TAT-HSP27) rapidly elevated HSP27 levels in brain microvessels and ameliorated I/R-induced BBB disruption and subsequent neurological deficits. Thus, the present study demonstrates that HSP27 can function at the EC level to preserve BBB integrity after I/R brain injury. HSP27 may be a therapeutic agent for ischemic stroke and other neurological conditions involving BBB breakdown.

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Section: Ec-specific Overexpression Of Hsp27 Ameliorates Bbb Disruptionmentioning

confidence: 99%

Endothelium-targeted overexpression of heat shock protein 27 ameliorates blood–brain barrier disruption after ischemic brain injury

Shi

Jiang

Zhang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

118

144

View full text Add to dashboard Cite

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“…To date, numerous neurological disorders have been the subject of examination for stem cell therapy, with highly encouraging results alluding to its efficacy as a stroke treatment [3], [4], [5]. The current availability of a single stroke treatment - thrombolytic agent tissue plasminogen activator (tPA) – has not slowed the disease from being a major cause of mortality and morbidity.…”

Section: Stem Cell Biology and Therapymentioning

confidence: 99%

Regulated and Unregulated Clinical Trials of Stem Cell Therapies for Stroke

Liska

Crowley

Borlongan

2017

Transl. Stroke Res.

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Several lines of laboratory investigations reporting solid safety profiles and robust efficacy readouts of stem cells in clinically relevant animal models have advanced stem cell transplantation as an experimental therapy for stroke. Unfortunately, translating laboratory findings into effective clinical trials entails rigorous regulatory examinations, which posed a major challenge in the application of stem cells to patients. As a consequence of this slow pace of clinical entry, and a media-propagated hype narrating stem cells as a “magic bullet”, a dangerous market has been created for unregulated stem cell clinics. These clinics are often guilty of misleading patients and delivering low-quality, even harmful, treatments. Additionally, these medical tourism-purported clinical procedures, which have been performed even in the US, are likely to negatively impact on the true science and clinical value of stem cells. For the full potential of stem cell therapies to be realized, these pressing public misconceptions and regulatory clinical concerns must be addressed. Here, we provide the scientific evidence supporting the safe and effective conduct of stem cells. Arguably, relying on such evidence-based science to dictate the translation of stem cells from the laboratory to the clinic should allow an objective assessment of the risks and the rewards, and the delineation of the hype from hope of this experimental stroke therapy.

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“…Small sample sizes aggravated the problem by often being insufficient to detect small or even moderate, but clinically relevant functional improvements. On the other hand, widely employed rodent studies may overestimate functional recovery effects since rodents exhibit a considerable capacity to compensate functional deficits, often presenting functionally Bnormal^when applying less sensitive tests [14].…”

Section: The Dominance Of Functional Endpointsmentioning

confidence: 99%

Academic-industry Collaborations in Translational Stroke Research

Boltze

Wagner

Barthel

et al. 2016

Transl. Stroke Res.

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Academic-industry collaborations are an emerging format of translational stroke research. Next to classic contract research models, a multitude of collaboration models has been developed, some of which even allowing for multinational or intercontinental research programs. This development has recently been paralleled by first successful attempts to overcome the translational stroke research road block, such as the unprecedented success of novel endovascular approaches or the advent of the multicenter preclinical trial concept. While the first underlines the role of the industry as a major innovation driver in stroke research, the latter will require enrollment of industrial partners for optimal output. Moreover, academic-industry partnerships are invaluable to bridge the translational "valley of death" as well as funding gaps in times of dwindling public funding and declining high risk capital investments. However, these collaborations are also subject to relevant challenges because interests, values, and aims often significantly differ between cademia and industry. Here, we describe common academic-industry collaboration models as well as associated benefits and challenges in the stroke research arena. We also suggest strategies for improved planning, implementation, guidance, and utilization of academic-industry collaborations to the maximum mutual benefit.

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Mesenchymal Stromal Cells in Stroke: Improvement of Motor Recovery or Functional Compensation?

Cited by 51 publications

References 10 publications

Endothelium-targeted overexpression of heat shock protein 27 ameliorates blood–brain barrier disruption after ischemic brain injury

Endothelium-targeted overexpression of heat shock protein 27 ameliorates blood–brain barrier disruption after ischemic brain injury

Regulated and Unregulated Clinical Trials of Stem Cell Therapies for Stroke

Academic-industry Collaborations in Translational Stroke Research

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