Therapeutic Potential of Human Induced Pluripotent Stem Cells in Experimental Stroke

Abstract

Ischemic stroke mainly caused by middle cerebral artery occlusion (MCAo) is a major type of stroke, but there are currently very limited therapeutic options for its cure. Neural stem cells (NSCs) or neural precursor cells (NPCs) derived from various sources are known to survive and improve neurological functions when they are engrafted in animal models of stroke. Induced pluripotent stem cells (iPSCs) generated from somatic cells of patients are novel cells that promise the autologous cell therapy for stroke. In this study, we successfully differentiated iPSCs derived from human fibroblasts into NPCs and found their robust therapeutic potential in a rodent MCAo stroke model. We observed the significant graft-induced behavioral recovery, as well as extensive neural tissue formation. Animal MRI results indicated that the majority of contralaterally transplanted iPSC-derived NPCs migrated to the peri-infarct area, showing a pathotropism critical for tissue recovery. The transplanted animals exhibited the significant reduction of stroke-induced inflammatory response, gliosis and apoptosis, and the contribution to the endogenous neurogenesis. Our results demonstrate that iPSC-derived NPCs are effective cells for the treatment of stroke.

Neural Stem Cells in Stroke: Intracerebral Approaches

“…Preclinical stroke studies have confirmed the ability of iPSC-derived NSCs to enhance stroke recovery following IC delivery [44][45][46][47], including in neonatal stroke [48], and have further shown that iPSC-derived NSCs can differentiate into multiple types of functionally active neurons following IC delivery into the stroke-injured brain [45,46]. Similar to embryonic-derived NSCs, the potential to form tumors or ectopic tissue by iPSC-derived NSCs remains a concern, prompting development of methods to generate induced NSCs (iNSCs) or induced neuronal (iN) cells directly from somatic cells without initial reversion to a pluripotent state [49,50].…”

Induced Pluripotent Stem-Cell-Derived Neural Cell Types in Treatment of Stroke

“…Previous studies by Kawai et al and Chen et al showed that transplantation of undifferentiated stem cells into middle cerebral artery occlusion (MCAO) DNA deoxyribonucleic acid, mRNA messenger ribonucleic acid stroke models led to the development of large tumors containing cells of the ectoderm, endoderm, and mesoderm lineages [47,48]. The differentiation of iPSCs into iNSCs has been successfully achieved using a number of different protocols originally developed for hESCs [7][8][9][10]. Oki et al utilized a previously developed ESC approach where iPSCs were detached and grown in suspension as EBs to enhance spontaneous differentiation [9,49].…”

“…These spheres were then plated on poly-ornithine and laminin-coated dishes in serum-free media with derived cells being a homogeneous population of NSCs. Other groups have used similar systems with variations including the addition of unique growth factors, inhibitors, supporting stromal cells (e.g., PA6) and changes in timing of differentiation steps [7,8]. Despite the variability in protocols, iNSCs are SOX1 and Nestin positive and should be capable of differentiating into multiple lineages of neurons and glia.…”

“…iPSCs are highly plastic and can be easily differentiated into neural stem cells (NSCs) that can be expanded to someday provide the volume of cells needed for therapeutic applications. Data in rodent stroke models have been very positive with induced pluripotent stem-cell-derived neural stem cell (iNSC) transplantations leading to functional recovery and decreased infarct sizes [7][8][9][10]. However, many challenges and questions remain before iNSC cell therapies can be deemed a safe and effective treatment in human patients.…”

“…Recent studies have demonstrated that iNSCs may serve as an excellent regenerative therapy with a dual function: (1) acting as a cell-replacement therapy and as (2) a producer of regenerative paracrine factors (e.g., vascular endothelial growth factor, VEGF) that enhance endogenous tissue regeneration in rodent stroke models [7][8][9][10][21][22][23] (Fig. 10.1).…”