Limited treatments are available for perinatal/neonatal
stroke. Induced pluripotent stem cells (iPSCs) hold therapeutic promise for
stroke treatment, but the benefits of iPSC
transplantation in neonates are relatively unknown. We hypothesized that transplanted iPSC-derived neural progenitor cells (iPSC-NPCs) would increase regeneration after
stroke. Mouse pluripotent iPSCs were differentiated into neural progenitors using a
retinoic acid protocol. Differentiated neural cells were characterized by using multiple criteria and assessments.
Ischemic stroke was induced in postnatal day 7 (P7) rats by occluding the right middle cerebral artery and right common carotid artery. iPSC-NPCs (400,000 in 4 µl) were transplanted into the penumbra via intracranial injection 7 days after
stroke. Trophic factor expression in the peri-
infarct tissue was measured using Western blot analysis. Animals received daily
bromodeoxyuridine (
BrdU)
injections and were sacrificed 21 days after
stroke for immunohistochemistry. The vibrissae-elicited forelimb placement test was used to evaluate functional recovery. Differentiated iPSCs expressed mature neuronal markers, functional
sodium and
potassium channels, and fired action potentials. Several angiogenic and neurogenic trophic factors were identified in iPSC-NPCs. Animals that received iPSC-NPC
transplantation had greater expression of
stromal cell-derived factor 1-α (SDF-1α) and
vascular endothelial growth factor (
VEGF) in the peri-
infarct region. iPSC-NPCs stained positive for neuronal nuclei (NeuN) or
glial fibrillary acidic protein (GFAP) 14 days after
transplantation. iPSC-NPC-transplanted animals showed greater numbers of
BrdU/NeuN and
BrdU/
Collagen IV colabeled cells in the peri-
infarct area compared with
stroke controls and performed better in a sensorimotor functional test after
stroke. iPSC-NPC
therapy may play multiple therapeutic roles after
stroke by providing trophic factors, increasing angiogenesis and neurogenesis, and providing new cells for tissue repair.