Ischemic stroke is caused by thrombogenesis and embolism in the intracranial artery and account for approximately 85% of all stroke events. The pathophysiology of ischemic stroke involves interrelated and coordinated processes such as loss of cellular ion homeostasis, free radical-mediated toxicity, cytokine-mediated toxicity, inflammation, disruption of the blood-brain barrier (BBB), and infiltration of leukocytes. Ischemic stroke can be divided into three pathological phases based on the time course of its development: acute (hours), subacute (hours to days), and chronic (days to months). During the acute phase, the BBB is disrupted, and neutrophils adhere to the endothelium, where they release superoxide anions that eventually trigger inflammation and tissue damage. Within the subacute phase, multiple genes are activated and tissue damage is apparent. Pathologically, the ischemic areas include an infarct core, which consists of dead cells and tissue, and a peri-infarct area, the penumbra. During the chronic phase, limited neurogenesis and angiogenesis processes are initiated.
Clinical cell therapy approaches for the treatment of ischemic stroke focus on neuroprotection, cell replacement and angiogenesis induction using different cell types: bone marrow-derived mesenchymal stem cells (BM-MSCs), bone marrow-derived endothelial progenitor cells (BM-EPCs), bone marrow-derived mononuclear cells (BM-MNCs), which contains a sub-population of CD34+ cells, neural precursor cells (NPCs), and olfactory ensheathing cells (OECs).
Bone marrow-derived mesenchymal stem cells (BM-MSCs), also termed bone marrow mesenchymal stromal cells, reside in the bone marrow and support hematopoiesis. BM-MSCs bear significant potential as therapeutic candidates for stroke, since they can be easily harvested from bone marrow or peripheral blood, can be rapidly expanded ex vivo and are known to be allogeneic and non-immunogenic, thereby eliminating risk of rejection.
In stroke animal models, intravenously infused mesenchymal stem cells (MSCs) targeted the ischemic hemisphere, specifically the areas around the lesion, also termed the ischemic boundary zone (IBZ). There, they expressed neuron, astrocyte-, and endothelial cell-specific markers. In addition, MSCs increased the expression of neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and nerve-growth factor (NGF) in the ischemic tissue, led to decreased apoptosis in the IBZ, and promoted proliferation of endogenous cells in the subventricular zone. In addition, MSCs supported angiogenesis in the IBZ, by secretion of the angiogenic growth factor placental growth factor (PGF), and by elevation of the levels of both endogenous vascular endothelial growth factor (VEGF) and its receptor VEGFR2.
When MSCs were intravenously injected into stroke patients, they were shown to promote functional recovery and to improve neurological outcomes, as determined by the Barthel index and modified Rankin score.
Bone marrow-derived endothelial progenitor cells (BM-EPCs) are defined as bone marrow (BM)-derived immature cells with the ability to differentiate into mature endothelial cells. EPCs are characterized by the expression of hematopoietic stem cell (HSC) markers, such as CD34, and by the expression of KDR, an endothelial cell marker. Since the number of EPCs is reduced in disease conditions and ischemia, transfusion of exogenous EPCs was suggested to be a possible cell therapy for the treatment of stroke. It was shown that transplantation of CD34+ cells (EPC-rich subpopulation) after ischemic stroke promoted angiogenesis and neurogenesis after ischemic stroke. Moreover, they induced a decrease in cell apoptosis, increased angiogenesis and neurogenesis, and improved functional recovery.
Neural progenitor cells (NPCs), also termed neural stem cells (NSCs), can be isolated from embryonic and fetal rodent and human brains. Intracerebral, intraventricular, or intravenous administration of mouse NPCs to post-ischemic rats, resulted in NSCs migration to the ischemic brain regions and to expression of neuronal or neuroepithelial markers, such as NeuN and nestin. Similarly, human fetal NPCs migrated to ischemic regions and expressed neuroblast and immature neuronal markers when injected into ischemic rodent brains. In addition, human fetal NPCs exhibitied robust survival potential, expressed mature neuronal markers such as HuD, calbindin, and parvalbumin, and led to a reduction in the infarct volume and behavioral improvement, when injected into rodent ischemic brains.
Olfactory ensheathing cells (OECs) are a unique glial cell type, that reside in the olfactory bulb and olfactory mucosa. These cells were found around axonal bundles of olfactory neurons emanating from the olfactory mucosa into the olfactory bulb. OECs have been extensively studied in animal models of spinal cord injury (SCI), and were shown to promote regeneration and remyelination of injured spinal cord axons. Intracranially infused OECs in MCAO animal models, showed long-term survival, long-distance migration capacities, significantly decreased mortality rates, and improved myelination and animal behavior.
Recent clinical trials utilize BM-MSCs, BM-EPCs and umbilical cord blood cells for the treatment of ischemic stroke in humans. In most clinical trials, autologous cells are introduced into the patient via intravenous infusion. For example, a phase 2 clinical trial, currently conducted at the university hospital of Grenoble, utilizes bone marrow-derived stem cells to treat stroke patients.