Effects of Administration Route on Migration and Distribution of Neural Progenitor Cells Transplanted into Rats with Focal Cerebral Ischemia, an MRI Study

Abstract

We tested the hypotheses that administration routes affect the migration and distribution of grafted neural progenitor cells (NPCs) in the ischemic brain and that the ischemic lesion plays a role in mediating the grafting process. Male Wistar rats (n = 41) were subjected to 2-h middle cerebral artery occlusion (MCAo), followed 1 day later by administration of magnetically labeled NPCs. Rats with MCAo were assigned to one of three treatment groups targeted for cell transplantation intra-arterially (IA), intracisternally (IC), or intravenously (IV). MRI measurements consisting of T2-weighted imaging and three-dimensional (3D) gradient echo imaging were performed 24 h after MCAo, 4 h after cell injection, and once a day for 4 days. Prussian blue staining was used to identify the labeled cells, 3D MRI to detect cell migration and distribution, and T2 map to assess lesion volumes. Intra-arterial (IA) administration showed significantly increased migration, a far more diffuse distribution pattern, and a larger number of transplanted NPCs in the target brain than IC or IV administration. However, high mortality with IA delivery (IA: 41%; IC: 17%; IV: 8%) poses a serious concern for using this route of administration. Animals with smaller lesions at the time of transplantation have fewer grafted cells in the parenchyma.

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

“…Systematic studies on NPC-induced neuroprotection against cerebral ischemia after both systemic and local transplantation do not exist apart from the aforementioned works [33,34]. Since our study indicates that systemic transplantation of native and transduced NPCs resulted in sustained neuroprotection despite low intracerebral numbers of grafted cells, NPC-induced modulation of extracerebral injurious mechanisms might be intriguing.…”

“…Until recently, only two studies systematically compared the effect of different NPC transplantation routes on postischemic outcome. However, these studies are limited to a maximal observation period of 1 week and lack an analysis of underlying cellular mechanisms [33,34].…”

Rescuing the neonatal brain from hypoxic injury with autologous cord blood

“…injection, carotid artery injection of neural progenitors, mainly conducted in the adult stroke model, resulted in a higher level of cellular survival and engraftment in the injured brain. 113,114 However, the risk of approach via carotid injection has been reduction in cerebral blood flow and consequently microstrokes. 114,115 Such an approach, via the carotid, is much too risky to consider at this early stage of clinical trials of cells for neonates with HIE.…”

“…113,114 However, the risk of approach via carotid injection has been reduction in cerebral blood flow and consequently microstrokes. 114,115 Such an approach, via the carotid, is much too risky to consider at this early stage of clinical trials of cells for neonates with HIE. Nasal administration may represent another novel route of stem cell delivery to the ischemic brain in newborns.…”

Clinical trial design for stem cell therapies in stroke: What have we learned?

“…51 The intravenous route is more feasible and acceptable, and justified on the basis of changes in our understanding of the biology of cell therapy in the acute or early subacute time window. The intraarterial route may allow modest (although likely transient) engraftment of cells but comes at the probable expense of greater complications 52 and more challenging recruitment unless piggy-backed on hyperacute endovascular thrombectomy. Whether this is feasible or not remains to be established.…”