Abstract
Stroke is a major neurovascular disorder threatening human life and health. Very limited clinical treatments are currently available for stroke patients. Stem cell transplantation has shown promising potential as a regenerative treatment after ischemic stroke. The present investigation explores a new concept of mobilizing endogenous stem cells/progenitor cells from the bone marrow using a parathyroid hormone (PTH) therapy after ischemic stroke in adult mice. PTH 1-34 (80 µg/kg, i.p.) was administered 1 hour after focal ischemia and then daily for 6 consecutive days. After 6 days of PTH treatment, there was a significant increase in bone marrow derived CD-34/Fetal liver kinase-1 (Flk-1) positive endothelial progenitor cells (EPCs) in the peripheral blood. PTH treatment significantly increased the expression of trophic/regenerative factors including VEGF, SDF-1, BDNF and Tie-1 in the brain peri-infarct region. Angiogenesis, assessed by co-labeled Glut-1 and BrdU vessels, was significantly increased in PTH-treated ischemic brain compared to vehicle controls. PTH treatment also promoted neuroblast migration from the subventricular zone (SVZ) and increased the number of newly formed neurons in the peri-infarct cortex. PTH-treated mice showed significantly better sensorimotor functional recovery compared to stroke controls. Our data suggests that PTH therapy improves endogenous repair mechanisms after ischemic stroke with functional benefits. Mobilizing endogenous bone marrow-derived stem cells/progenitor cells using PTH and other mobilizers appears an effective and feasible regenerative treatment after ischemic stroke.
Highlights
According to recent statistics, stroke is the fourth leading cause of human death and the number one cause of disability in the adult population in the United States [1]
We focused on CD34 and Flk1 positive (CD34+/Flk+) cells that are well characterized as bone marrow derived endothelial stem cells (ESCs)/endothelial progenitor cells (EPCs)
We examined the effects of parathyroid hormone (PTH) administration on bone marrow stem cell mobilization and its effects on regenerative mechanisms after focal cerebral ischemic stroke
Summary
Stroke is the fourth leading cause of human death and the number one cause of disability in the adult population in the United States [1]. Approximately 5.7 million people each year die from stroke worldwide [2]. 87% suffer from ischemic stroke [1]. Healthcare and social burden of stroke, stroke treatment is still limited to thrombolytic therapy using tissue plasminogen activator (tPA) with a narrow time window of 4.5 hrs after the onset of ischemic attack. For stroke survivors, during the sub-acute and chronic phases, only supportive care and rehabilitation are available with uncertain partial recovery. Stroke represents a clinical entity that requires more innovative treatments both for acute neuroprotection and for regenerative tissue repair
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