Survival and Differentiation of Transplanted Neural Stem Cells Derived from Human Induced Pluripotent Stem Cells in A Rat Stroke Model

Abstract

Introduction Although administration of various stem cells has shown promise in stroke models, neural stem cells (NSCs) derived from human induced pluripotent stem cells (iPSCs) have advantages over other cell types. We asked if these cells could survive, differentiate, and improve stroke recovery in an ischemic stroke model. Methods Human iPSCs were induced in vitro to an early NSC stage. One week after focal cerebral ischemia, 20 rats received cells or vehicle by intracerebral injection. Graft cell fate, infarct volume, and behavioral deficits were assessed. Results Graft cells were found in 8 of the transplanted rats (80%), with estimated mean graft cell numbers nearly double the amount transplanted one month later. Graft cells also expressed markers of NSCs in 5 rats (63%), neurons in all 8 rats (100%), rare astrocytes in 4 rats (50%), and signs of proliferation in 4 rats (50%), but no tumor formation was observed. Stroke volume and behavioral recovery were similar between groups. Discussion To our knowledge this is the first report of transplantation of NSCs derived from human iPSCs in a stroke model. Human iPSC-derived NSCs survived in the post-ischemic rat brain and appeared to differentiate, primarily into neurons. This cell transplantation approach for stroke appears to be feasible, but further optimization is needed.

Human-Induced Pluripotent Stem Cells form Functional Neurons and Improve Recovery After Grafting in Stroke-Damaged Brain

“…The studies with human iPSCs in stroke published so far provided no evidence for the formation of neuroblasts or morphologically mature neurons [25,26]. We found that at 4 months after human iPSC-derived lt-NES cells had been implanted into the striatum or cerebral cortex of Tcell-deficient rats in two different models of stroke, 73% and 77%, respectively, of grafted cells expressed the mature neuronal marker NeuN.…”

“…Finally, human fibroblastderived iPSCs implanted into the striatum of stroke-damaged rats were found to improve short-term sensorimotor recovery, but whether any neurons were formed is unclear [25]. Another recent study did not detect any effect of iPSCs on strokeinduced behavioral impairments at 4 weeks after transplantation [26]. The long-term consequences after transplantation of human iPSC-derived cells in the stroke-damaged brain, if they can differentiate in vivo to morphologically and functionally mature neurons, establish connections to target areas, and improve behavioral deficits resembling those in stroke patients, are currently unknown.…”

Neural differentiation from pluripotent stem cells: The role of natural and synthetic extracellular matrix

“…Raghavan et al [61] , 2013 also been shown to engraft with little neuroblasts or morphologically mature neurons in a rat model [55,56] . Recently, transplantation of hiPSC-derived NSCs exhibited functional recovery and electrophysiological properties of mature neurons, and was proved to be a safe approach for neuron replacement in stroke-damaged brain [53] .…”

Role of neural precursor cells in promoting repair following stroke

“…These promising results have led to an ongoing Phase I clinical trial of intracranial transplantation of embryonic stem cellderived neural stem cells in patients with subcortical/basal ganglia stroke [48] . More recently, iPSC-derived NPCs have also been shown to produce mature neurons, though no functional assessments were examined [49] . Studies that employed adult NPCs isolated from the SVZ and expanded in neurospheres have also shown NPC survival and differentiation after transplantation, although their survival is lower than NPCs derived from embryonic neural precursors [50][51][52] .…”