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Regenerative medicine is an emerging branch of medicine with the goal of restoring organ and/or tissue function for patients with serious injuries or chronic disease in which the bodies own responses are not sufficient enough to restore functional tissue. New and current Regenerative Medicines can use stem cells to create living and functional tissues to regenerate and repair tissue and organs in the body that are damaged due to age, disease and congenital defects. Stem cells have the power to go to these damaged areas and regenerate new cells and tissues by performing a repair and a renewal process, restoring functionality. Regenerative medicine has the potential to provide a cure to failing or impaired tissues. 

Cell therapy is a sub-type of regenerative medicine. Cell therapy (or cellular therapy) is defined as the administration of live whole cell or maturation of a specific cell population in a patient for the treatment of a disease. Cell therapy based on stem cells describes the process of introducing stem cells into tissue to treat a disease. Several specific sub-types of stem cells have been developped through successive research programmes initiated in 1970s: hematopoietic stem cells (HSCs) have been widely used for allogeneic cell therapy while pluripotent embryonic stem (ES) cells, isolated from the inner cell mass of early embryos has provided a powerful tool for biological research as these can differentiate into almost any cell lineage. However, ethical issues related to their isolation have limited their use in clinical research programs fo which mesenchymal stem cells (MSCs) are often prefered. These cells,first isolated and characterized by Friedenstein and colleagues in 1974, are a subset of non-hematopoietic adult stem cells that originate from the mesoderm (the middle layer of cells or tissues of an embryo, or the parts derived from this (e.g. cartilage, muscles, and bone). They possess self-renewal ability and multilineage differentiation into a wide variety of cells and tissues. MSCs exist in almost all tissues and can be easily isolated from the bone marrow, adipose tissue, the umbilical cord, fetal liver, muscle, and lung.

MSCs have displayed great potential in treating a large number of immune and non-immune diseases. However, there are still major questions concerning the optimal dosage of MSCs, routes of administration, best engraftment time and the fate of the cells after infusion. Thus, it is critical to explore the mechanisms governing MSC-based therapies. Although a uniform mechanism has not yet been discovered, the available data have revealed several working models for the beneficial effects of MSCs. 

Cell therapy for stroke

A promising approach for the treatment of stroke is activation of brain repair mechanisms and enhancement of spontaneous functional recovery. The major advantage of such restorative therapies is the extended therapeutic time window up to several weeks or months after the initial insult. This makes the treatment available to a much larger number of stroke patients. Cell-based restorative therapies have emerged as one attractive approach for the treatment of stroke. Transplanted cells, an example of “plastic” biological products, can adapt to different local conditions in damaged brain tissue while not being limited to a unique target. They can act on a wide range of endogenous protective and brain repair processes including immunomodulation, neuronal, vascular and glial remodeling. Two main treatment strategies can be distinguished: paracrine trophic support or direct neural replacement. The route, dose, and timing for cell administration after stroke are still debated, depending on the chosen cell product and the expected therapeutic effect. Today, the great variety of available cell types and sources form a rich therapeutic arsenal for stroke which requires, prior to clinical use, careful consideration regarding their respective preclinical safety and efficacy profiles, cell characterization, mechanisms of action, delivery routes and in vivo biodistribution properties.

The number of clinical trials that made use of MSCs has been rising since 2004. To date, 493 MSC-based clinical trials, either complete or ongoing, are registered in the international clinical trials database. With the advancement of preclinical studies, MSCs have been shown to be effective in the treatment of many diseases, including both immune diseases and non-immune diseases. Out of these, 25 phase I/II trials are on-going involving cell therapies in stroke. Several cell products and routes are investigated: intracerebral or intrathecal transplantation of neural stem cells or immortalized neurons, IV injection of autologous MSC, IC5, IA or IV injections of autologous mononuclear cells, IC transplantation of hematopoietic stem cells / endothelial progenitors CD34+ from autologous blood and IV injection of placenta derived stem cells. Only one unpublished trial directly compared IA vs IV injection of autologous MNC. Recently, one trial focused on intracerebral haemorrhage using IC injection of MNC from autologous bone marrow202. The meta-analysis of 9 controlled clinical trials suggests some efficacy of cell therapy to improve stroke recovery. 

For the development of regenerative therapies for stroke, additional translational studies should be conducted to evaluate efficay against various stroke types and localization, evaluate the importance of usual vascular risk factors, such as hypertension, diabetes, and cerebral small artery disease, and concomitant treatments, such as tPA thrombolysis or statins. Lesion location and size will be important factors to determine which patients are suitable for cell therapy. For example, IV MSC could be less efficient in treating stroke patients with a lesion including the SVZ. Concerning stroke type, little data are available concerning haemorrhagic stroke. Despite benefits seen in experimental studies of MSC IA or IV injections, it remains unclear if clinical trials should include both haemorrhagic and ischemic strokes regarding differences in pathophysiology and recovery. Concerning risk factors, recent studies have suggested that IV injection of MSC given 24h post-stroke induces adverse effects in diabetic rats increasing blood-brain barrier leakage and vascular damage via increased expression of angiogenin. Negative results were also reported in hypertensive rats after acute IV injection of bone marrow MNCs or cord blood cells. Otherwise, the combination of simvastatin and cord blood cell IV injection 24h post-stroke increased BDNF/TrkB expression, enhanced cell migration towards the ischemic brain tissue, and amplified synaptogenesis, improving recovery.

Mechanisms of action

The functional benefits of cell therapy on stroke recovery are well established in animal models using the above-mentioned cell types coupled with different delivery routes. However, their respective mechanisms of action are complex and vary according to the transplanted cell type. A common characteristic of these cell products is that they simultaneously target many different host brain cell types, including NSCs, neurons, endothelial and glial cells, leading to improvements via several endogenous repair mechanisms, such as neuro-glio-angiogenesis, axonal sprouting, synaptogenesis. Direct replacement of injured neurons (“homotopic” repair) has been suggested after NSC IC or IA injection encouraging possible long-term survival of implanted neurons in human, after iPSC derived neuron, bone marrow cell or ESC-derived MSC injection. However, only a few grafted cells can be expected to express neuronal markers, so long-term graft survival is poor. Moreover, despite possible integration of grafted NSCs into the host circuitry, quite often immediate functional recovery is seen not likely to be caused by newly formed neurons and synapses. Additionally, as emphasized for IV-injected cord blood cells, cell entry or integration into the host brain would not be required to obtain brain repair enhancement. Concerning HSC, the possibility of their efficient differentiation into neurons is still debated. Direct replacement of all damaged brain cells, including cells from ectoderm such as neurons or glia, and mesoderm such as microglia or endothelium), would require transplantation of “native” pluripotent cells (ESC or iPSC) which might result in tumor formation.

Mode of action of MSCs for stroke
Potential neuroprotective and neurorestorative effects of mesenchymal stem cells (MSCs).
Source: Castillo-Melendez et al, Frontiers in Neuroscience, 

Thus, it seems more realistic to expect that cell therapy, notably employing “non-neural” cells, such as MSC, works through paracrine trophic support effects on the injured brain by secreting various growth factors. The improvement in host brain plasticity and associated recruitment of endogenous progenitors has been identified after injection of MSC via the sonic hedgehog pathway, NSC notably by enhancing dendritic plasticity, or olfactory ensheathing cells. Moreover, the effects of cell therapies on post-stroke vasculogenesis and angiogenesis seem to be crucial in explaining early post-graft benefits. IC injection of endothelial cells can improve vasculogenesis linked to neurogenesis via VEGF release mechanisms. Proangiogenic effects were also observed early after injection of MSC that can contribute to VEGF-induced angiogenesis by supplying metalloprotease MMP-9, after injection of NSC, EP, or cord-blood MNC CD34+104. These MNCs contain EP and smooth muscle progenitors which may collaborate to form a mature vascular network supporting and enhancing neuroblast survival and migration after stroke145. Moreover, EP, MSC or NSC could also facilitate protection or restoration of the blood-brain barrier after stroke.

Another important effect of cell therapy is enhanced glial remodeling and limitations in anterograde degeneration. For example, IV injection of MSC has beneficial effects on both post-stroke glial remodeling and axonal remyelination. It also increases GDNF levels, creating a hospitable environment for brain repair and neuroblast migration from the SVZ. Also cells can lessen the secondary pathology typical to stroke, i.e., the remote areas connected to the primary infarct will be affected. This takes place in delayed fashion offering a novel therapeutic target.

Finally, cell therapies can also limit host cell death through anti-apoptotic and immunomodulatory mechanisms. Although MSCs are known to attenuate microglia and leukocyte inflammatory responses after stroke156-158, some immunomodulation properties were also observed for cord blood cells or NSC which can both influence splenic inflammatory responses after stroke.

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