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Advanced Regenerative Medicine
Stroke
Stroke
Stroke is the most common cause of adult-acquired disability in the developed and developing world.
With an aging population, the incidence and prevalence of stroke are predicted to rise. Stroke is an acute-onset clinical syndrome that develops following a vascular insult to the brain.
Brain ischemia resulting from thromboembolism or less frequently, in situ thrombosis, constitutes 80%−85%, and haemorrhage resulting from hypertension or vessel wall pathology constitutes 15%−20% of all strokes.
Following vascular occlusion, a complex chain of events occurs at a molecular level, leading to irreversible tissue injury, including failure of energy synthesis, loss of transmembrane ionic gradients dependent on active transport, cell depolarization, and excitotoxicity due to the excess release of excitatory neurotransmitters.
In the region with severely reduced blood flow (the ischemic core), these processes result in rapid cell necrosis affecting all the cellular elements (neurons, glia, and blood vessels). A region around the core (the ischemic penumbra) transiently maintains a collateral blood supply sufficient for cell viability. Restoring perfusion can salvage penumbral tissue, and timely recanalization is the most robust predictor of good clinical prognosis following ischemic stroke.
Cell therapies act on multiple mechanisms in ischemic stroke, depending upon the timing and mode of administration; however, unlike neuroprotectant drugs, cell therapies have the advantage that they may be able to respond dynamically to an environment that varies both temporally and spatially after ischemia, rather than targeting a single pathway or mechanism of action.
Secretome
The use of MSCs for tissue repair was initially based on the hypothesis that these cells home to and differentiate within the injured tissue into specialized cells. However, it now appears that only a small proportion of transplanted MSCs actually integrate and survive in host tissues. Thus, the predominant mechanism by which MSCs participate in tissue repair seems to be related to their paracrine activity. Indeed, MSCs provide the microenvironment with a multitude of trophic and survival signals including growth factors and cytokines. Recent discoveries suggest that lipid microvesicles released by MSCs may also be important in the physiological function of these cells. Over the past few years the biological relevance of micro- and nano-vesicles released by cells in intercellular communication has been established. Alongside the conventional mediators of cell secretome, these sophisticated nanovesicles transfer proteins, lipids and, most importantly, various forms of RNAs to neighbouring cells, thereby mediating a variety of biological responses.
Preclinical studies regarding Stroke
Adipose-derived mesenchymal stromal cells (AD-MSCs) have high proliferative capacity and ability to secrete trophic factors. Although intra-arterial (IA) transplantation of stem cells induces efficient engraftment to the host brain, it is more and more clear that their long-term therapeutic effects is mediated by the secretome.
After induction of ischemia in rats by middle cerebral artery occlusion, human AD-MSCs were transplanted into their carotid arteries with the use of a micro-needle, and the therapeutic effects investigated during the early and late phases of ischemia by means of in vivo magnetic resonance imaging, functional and histological analyses.
During the early phase of cerebral ischemia, IA transplantation of AD-MSCs attenuated inflammation and enhanced endogenous neurogenesis. Transplanted animals showed a marked improvement in functional tests during the early phase of cerebral ischemia that was less prominent but still significant during the late phase of cerebral ischemia. Only a small number of engrafted cells survived at 8 weeks after transplantation and differentiated into neuronal, glial and endothelial cells.
Studies showed that intranasally delivered mesenchymal stem cells migrated to peri-injury regions and provided growth factors to increase neurogenesis after intracerebral haemorrhage (ICH) and concluded that intranasal administration of MSC is an effective treatment for ICH, and that it enhanced neuroregenerative effects and promoted neurological functional recovery after ICH.
Clinical studies on Stroke
For stem cell therapy to be useful in augmenting the recovery after stroke, it needs to be safe and effective, applicable to a broad spectrum of patients with stroke, and cost-effective.
Most clinical trials using various types of stem cell have demonstrated that stem cell therapy following stroke is both feasible and safe, and may improve recovery. However, these trials varied in terms of the patient characteristics, cell therapy timing, dose and type of cells delivered, and mode of treatment.
In addition, many factors that could be critical to the transplantation success, including the location and the extent of lesions, were not adequately considered. Moreover, the assessments of functional improvement, adverse effects, and pre-treatment screening tests for safety have varied greatly among the studies.
Newer studies have shown that transformation of ad MSC or engraftment in the brain is not necessary to show therapeutic efficacy.
The majority of therapeutic effects were due to the secretome containing cytokines and exosomes containing micro RNA.