Fig. 2.1
Integrated approach to outcomes/clinical trials. The three general approaches by which stem cells could exert a beneficial effect following stroke (1–3). The direct placement of exogenous (autologous or allogeneic) within the stoke cavity could either serve to redirect endogenous stem cells from the subventricular zone (SVZ) to the infarcted region, facilitating their local engraftment and/or trophic effects or the transplanted exogenous cells could contribute more directly by replacing cells in the peri-infarct region and/or providing for a more favorable local environment. Stem cells delivered remotely (e.g., intravenously) likely exert their effect at the blood–brain barrier (BBB) interface through the activation of second messengers and/or the release of trophic factors, exosomes, etc. that facilitate a more permissive environment within the peri-infarct region
Repair. In this context, there is consideration of immune response modulation, release of soluble trophic factors to create a more permissive environment either through local effects and/or niche upregulation, and instructing a specific endogenous stem cell fate. Facilitating a more permissive environment (reduced neuroinflammation, improved regional cerebral blood flow, either directly or through facilitating angiogenesis) should balance enhanced plasticity with the downregulation of inhibitory pathways that provide the CNS with the necessary feedback to maintain a homeostatic environment [16]. Mesenchymal stem cells have demonstrated experimental success in a number of pathologic scenarios. Such a broad protective/reparative effect suggests that these cells may be capable of releasing a diverse array of factors. Growth factors likely contribute to the beneficial effect [17], although much attention has recently focused on exosomes [18–20], a very heterogeneous group (both in size and content) of secreted lipid vesicles that may have therapeutic effects under a multitude of conditions. Although different exosomes may have competing actions, this is an area of medicine that provides both a rationale for the beneficial effect(s) of MSCs and is spawning a novel field of both diagnostics and therapeutics to improve the recognition of tissue injury and aid in customized tissue repair following various pathologies.
Replacement (including trans-differentiation). Generally, long-term functional engraftment/integration of exogenous stem cells at the site of pathology is much more the exception than the rule [12, 21, 22]. Nonetheless, even the integration of a small percentage of stem cells into the infarct area may result in a meaningful improvement. It is not clear if there is one or more critical variables exhibited by certain stroke patients that may facilitate a more permissive environment. Genetic polymorphisms, concomitant medications, or overall medical status may contribute in ways that are currently unclear. Additionally, the endogenous secretion of trophic factors directly within the stroke/penumbral region may be an important mechanism for neural repair.
Redirection (scaffold, bridge). This is a relatively new concept and is a hybrid between the repair and replacement mechanisms. The exogenous stem cells are necessary prerequisites at the stroke site, facilitating the directed migration of endogenous stem cells to the site of injury [23]. The exogenously placed stem cells have a limited presence at the stroke site, although it appears that the endogenously migrated stem cells may be able to integrate and improve the brain cytoarchitecture in this region.
Even within each of the general strategies outlined above, there are multiple mechanisms by which a neurorestorative effect may be realized, just as there are multiple mechanisms that mediate the endogenous neuroplasticity that is constantly occurring. These include modulation of inhibitory circuits and facilitation of more permissive activities. The above discussion does emphasize that the “single” approach of stem cells is actually a pleiotropic strategy that may allow the field to move beyond the single MOA approach to address a very complex insult.
Certainly, any of the approaches mentioned would need to create the appropriate permissive environment that will allow for the differentiation and expression of any/all neuronal and glial types needed to reconstitute an effective and efficient network. This is irrespective of cellular augmentation by endogenous elements or through the delivery of exogenous stem cells (or both).
There are additional critical points for discussion when considering cell therapy for stroke:
Stem cell route of administration. To a large extent, the route of administration will be dictated by the purported role for stem cells as a poststroke therapy. Currently, many contemporary stem cell studies for stroke utilize intravenous delivery which is seen as more of a reflection of pragmatism than an understanding of their MOA. The limited ability of stem cells to cross the BBB would not be an impediment to peripheral (intravenous or intra-arterial) administration [15] if the primary role of the stem cell was to provide second messenger signaling or growth factors that would then facilitate a more permissive environment for brain repair (e.g., shed exosomes have demonstrated the ability to cross the BBB). There are animal model data to suggest that the intravenous administration of stem cells may be as efficacious as administering stem cells directly to the injured region of the brain. A direct comparison of different delivery routes within the same animal model may be of great value and would not necessarily demand translatability to the clinical scenario. Alternatively, if the pluri- or multipotent stem cells are intended to serve as replacement cells in the infarct region, or if the intent is to serve as a biobridge from internal sources of neurogenesis to the stroke region, then strategies must be developed to stereotactically deliver the cells to the appropriate brain region.
Stem cell timing of delivery. Ischemic brain injury is accompanied by a major inflammatory response which includes both CNS intrinsic (e.g., microglial upregulation) and extrinsic (e.g., leukocyte and cytokine upregulation) activation [24]. The inflammatory response can be seen as either well orchestrated or, alternatively, well-intentioned but suboptimally regulated. A critical question is when to intervene with a stem cell therapy. If the ongoing (at least initial) inflammatory response is beneficial for self-repair (e.g., removal of necrotic debris, facilitation of a more permissive environment), then the early downregulation may be counterproductive. The ultimate answer may only be understood through direct intervention and rigorous, methodical assessment of relevant clinical (and possibly imaging/biochemical) endpoints.Related posts:
Induced Pluripotent Stem Cells as a Cell-Based Therapeutic in Stroke
Clinical Development of MultiStem® for Treatment of Injuries and Diseases of the Central Nervous System
Stem Cell Therapy for Neonatal Hypoxic–Ischemic Brain Injury
Neural Stem Cells in Stroke: Intracerebral Approaches
Intra-arterial Approaches to Stem Cell Therapy for Ischemic Stroke
Pathophysiology of Traumatic Brain Injury: Rationale and Role for Cellular Therapies
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