Survival, migration and neuronal differentiation of human fetal striatal and cortical neural stem cells grafted in stroke‐damaged rat striatum

Abstract

Stroke is a neurodegenerative disorder and the leading cause of disability in adult humans. Treatments to support efficient recovery in stroke patients are lacking. Several studies have demonstrated the ability of grafted neural stem cells (NSCs) to partly improve impaired neurological functions in stroke-subjected animals. Recently, we reported that NSCs from human fetal striatum and cortex exhibit region-specific differentiation in vitro, but survive, migrate and form neurons to a similar extent after intrastriatal transplantation in newborn rats. Here, we have transplanted the same cells into the stroke-damaged striatum of adult rats. The two types of NSCs exhibited a similar robust survival (30%) at 1 month after transplantation, and migrated throughout the damaged striatum. Striatal NSCs migrated farther and occupied a larger volume of striatum. In the transplantation core, cells were undifferentiated and expressed nestin and, to a lesser extent, also GFAP, betaIII-tubulin, DCX and calretinin, markers of immature neural lineage. Immunocytochemistry using markers of proliferation (p-H3 and Ki67) revealed a very low content of proliferating cells (<1%) in the grafts. Human cells outside the transplantation core differentiated, exhibited mature neuronal morphology and expressed mature neuronal markers such as HuD, calbindin and parvalbumin. Interestingly, striatal NSCs generated a greater number of parvalbumin+ and calbindin+ neurons. Virtually none of the grafted cells differentiated into astrocytes or oligodendrocytes. Based on these data, human fetal striatum- and cortex-derived NSCs could be considered potentially safe and viable for transplantation, with strong neurogenic potential, for further exploration in animal models of stroke.

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

“…The SC121 antibody labels >90% of human neural cells and does not cross-react with rat cells [7,9]. Grafted GFPþ cells that exhibited clear morphological characteristics of migrating neuroblasts (Fig.…”

“…Electrophysiological recordings showed mature neuronal properties of the grafted cells and signs of synaptic integration into host brain [5,6]. Human fetal NSCs also gave rise to mature neurons after transplantation into the stroke-damaged rat brain [7][8][9]. Transplanted NSCs may promote recovery without differentiating to neurons through several other mechanisms, for example, modulation of inflammation [10][11][12], neuroprotection [12], stimulation of angiogenesis [11,13,14], and enhancing brain plasticity [15][16][17].…”

Neural Stem Cells: Exogenous and Endogenous Promising Therapies for Stroke

“…Quantification of cell survival is poorly reported. Reports, from the few studies that have attempted to quantify cell survival, range from 1% (Hicks et al, 2009) to 30% (Darsalia et al, 2007). Site of transplantation may be relevant to cell survival, with pathological evidence of 33.4 ± 6.1% viable cells when human fetal neural stem cells (hNSCs) were transplanted in non-ischemic tissue medial to the ischemic lesion (Kelly et al, 2004).…”

“…In addition to promote proliferation, it has been shown that human fetal striatum derived NSCs, transplanted as neurospheres, survive in stroke-damaged rat striatum, migrate toward the site of the injury, and differentiate into mature neurons in the absence of tumor formation (Darsalia et al, 2007).…”

Effect of transplantation of cell suspension from embryonic nervous tissue and bone marrow on postischemic cerebral angiogenesis and restoration of limb motor function in rats with experimental ischemic stroke

“…Therefore, growth factors, stem cells of different origins, means of genetic engineering and their combinations are used in clinical trials and experimental studies. Numerous experimental studies have demonstrated the positive impact of neurogenic stem cells (NSC) and bone marrow mesenchymal stem cells (BM-MSCs) on functional recovery of experimental animals after stroke modeling [11,12,15]. However, an effect of сells transplantation at stroke, including its effect on angiogenesis, has not been sufficiently studied.…”