Cell Number and Timing of Transplantation Determine Survival of Human Neural Stem Cell Grafts in Stroke-Damaged Rat Brain

Abstract

Neural stem cells (NSCs) derived from human fetal striatum and transplanted as neurospheres survive in stroke-damaged striatum, migrate from the implantation site, and differentiate into mature neurons. Here, we investigated how various steps of neurogenesis are affected by intrastriatal transplantation of human NSCs at different time points after stroke and with different numbers of cells in each implant. Rats were subjected to middle cerebral artery occlusion and then received intrastriatal transplants of NSCs. Transplantation shortly after stroke (48 hours) resulted in better cell survival than did transplantation 6 weeks after stroke, but the delayed transplantation did not influence the magnitude of migration, neuronal differentiation, and cell proliferation in the grafts. Transplanting greater numbers of grafted NSCs did not result in a greater number of surviving cells or increased neuronal differentiation. A substantial number of activated microglia was observed at 48 hours after the insult in the injured striatum, but reached maximum levels 1 to 6 weeks after stroke. Our findings show that the best survival of grafted human NSCs in stroke-damaged brain requires optimum numbers of cells to be transplanted in the early poststroke phase, before the inflammatory response is established. These findings, therefore, have direct clinical implications.

Transduction of Neural Precursor Cells with TAT-Heat Shock Protein 70 Chaperone: Therapeutic Potential Against Ischemic Stroke after Intrastriatal and Systemic Transplantation

“…The efficacy of stem and progenitor cell-based therapies is well established and has already lead to clinical trials [13,28,29,31,[48][49][50]. In this context, NPCs that can differentiate into both glia and neurons might be advantageous, albeit neural cell replacement seems to be not a prerequisite for cell- based stroke therapy [20].…”

“…Among different transplantation routes, intravenous cell delivery has been used due to its simplicity and clinical practicability [8,25,26], although achieving low intracerebral cell numbers [15,27]. Therefore, local intracerebral injections are widely used, which can enhance the number of transplanted intracerebral cells but lack clinical utility due to invasive delivery procedures [28][29][30][31][32]. Until recently, only two studies systematically compared the effect of different NPC transplantation routes on postischemic outcome.…”

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

“…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].…”

Dopamine Receptors in Human Embryonic Stem Cell Neurodifferentiation

“…Large numbers of transplanted neurons are necessary for their survival and integration into the host brain [15,16]. The number of surviving neurons in the host brain is considered the primary determinant of the efficacy of any cell replacement therapy, including the therapy of Parkinson's disease [17].…”