Abstract
BackgroundIdentification of juvenile protective factors (JPFs) which are altered with age and contribute to adult-onset diseases could identify novel pathways for reversing the effects of age, an accepted non-modifiable risk factor to adult-onset diseases. Since endothelial progenitor cells (EPCs) have been observed to be altered in stroke, hypertension and hypercholesterolemia, said EPCs are candidate JPFs for adult-onset stroke. A priori, if EPC aging plays a ‘master-switch JPF-role’ in stroke pathogenesis, juvenile EPC therapy alone should delay stroke-onset. Using a hypertensive, transgenic-hyperlipidemic rat model of spontaneous ischemic-hemorrhagic stroke, spTg25, we tested the hypothesis that freshly isolated juvenile EPCs are JPFs that can attenuate stroke progression and delay stroke onset.Methodology/Principal FindingsFACS analysis revealed that cd45- [cd34+/kdr+] EPCs decrease with progression to stroke in spTg25 rats, exhibit differential expression of the dual endodthelin-1/VEGFsp receptor (DEspR) and undergo differential DEspR-subtype specific changes in number and in vitro angiogenic tube-incorporation. In vivo EPC infusion of male, juvenile non-expanded cd45-[cd34+/kdr+] EPCs into female stroke-prone rats prior to stroke attenuated progression and delayed stroke onset (P<0.003). Detection of Y-chromosome DNA in brain microvessels of EPC-treated female spTg25 rats indicates integration of male EPCs into female rat brain microvessels. Gradient-echo MRI showed delay of ischemic-hemorrhagic lesions in EPC-treated rats. Real-time RT-PCR pathway-specific array-analysis revealed age-associated gene expression changes in cd45-[cd34+/kdr]EPC subtypes, which were accelerated in stroke-prone rats. Pro-angiogenic genes implicated in intimal hyperplasia were increased in stroke-prone rat EPCs (P<0.0001), suggesting a maladaptive endothelial repair system which acts like a double-edged sword repairing while predisposing to age-associated intimal hyperplasia.Conclusions/SignificanceAltogether, the data demonstrate that cd45-[cd34/kdr+]EPCs are juvenile protective factors for ischemic hemorrhagic stroke as modeled in the spTg25-rat model. The ability to delay stroke onset emphasizes the importance of EPC-mediated roles in vascular health for ischemic-hemorrhagic stroke, a high unmet need.
Highlights
Much research has focused on environmental risk factors for adult-onset diseases as a paradigm for prevention and intervention, the counterpart concept of ‘‘juvenile protective factors’’ is less studied but important
Our results support the hypothesis that non-expanded CD45[CD34+/KDR+]endothelial progenitor cells (EPCs) are juvenile protective factors which change with age, and are capable of attenuating spontaneous ischemichemorrhagic stroke progression when infused as freshly isolated juvenile EPCs at,4–86104 EPCs/kg peripheral infusion in older stroke-prone rats prior to the onset of stroke
This is much lower than the 0.5–1.06106 ex vivo-expanded CD45+ [CD34+/ KDR+]EPCs infused in 25g mouse models, or 2–46107 EPCs/kg [1,12]
Summary
Much research has focused on environmental risk factors for adult-onset diseases as a paradigm for prevention and intervention, the counterpart concept of ‘‘juvenile protective factors’’ is less studied but important. Juvenile protective factors (JPFs) are endogenous physiological factors – be it cells, proteins, nucleic acids, or biochemical equivalent – which prevent disease in the young but which undergo age-associated cumulative changes which contribute to adult-onset diseases. A priori, targeting the maintenance of juvenile protective factors comprises a mechanism-based paradigm for the prevention and intervention of diseases associated with aging, such as stroke, neurodegenerative and/or cardiovascular diseases. In this way, instead of aging being a non-modifiable risk factor, JPFs become a translational pathway to modifying the contribution of aging to disease pathogenesis. Since endothelial progenitor cells (EPCs) have been observed to be altered in stroke, hypertension and hypercholesterolemia, said EPCs are candidate JPFs for adult-onset stroke. Transgenichyperlipidemic rat model of spontaneous ischemic-hemorrhagic stroke, spTg25, we tested the hypothesis that freshly isolated juvenile EPCs are JPFs that can attenuate stroke progression and delay stroke onset
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