Endothelial progenitor cell-derived conditioned medium mitigates chronic cerebral ischemic injury through macrophage
Ya-Wen Cheng1, Ling-Yu Yang1, Yi-Tzu Chen1,2
1Division of Neurosurgery, Department of Surgery, National Taiwan University Hospital, No.7, Chung-Shan South Road, Taipei, 100, Taiwan.
Insights
Endothelial progenitor cell-derived conditioned medium (EPC-CM) shows promise for treating chronic cerebral ischemia (CCI). EPC-CM, particularly its key factor macrophage migration inhibitory factor (MIF), improves vascular and cognitive function by activating the AKT pathway.
Area of Science:
- Neuroscience
- Vascular Biology
- Regenerative Medicine
Background:
- Chronic cerebral ischemia (CCI) impairs brain function and is linked to neurodegenerative diseases.
- Endothelial progenitor cells (EPCs) aid vascular repair, but stem cell therapy has limitations.
- Investigating EPC-derived conditioned medium (EPC-CM) offers a potential cell-free therapeutic strategy.
Purpose of the Study:
- To evaluate the therapeutic effects of EPC-CM on impaired vasculature and neurological function in a rodent model of CCI.
- To identify the key therapeutic factors within EPC-CM and elucidate their underlying mechanisms.
Main Methods:
- EPC-CM was analyzed for key factors; candidate factors were validated in vitro using oxygen-glucose deprivation (OGD)-injured cells.
- The therapeutic effects of EPC-CM and identified factors were tested in a rat model of CCI induced by bilateral internal carotid artery ligation (BICAL).
- Vascular, motor, and cognitive functions were assessed post-treatment.
Main Results:
- Macrophage migration inhibitory factor (MIF) was identified as a key pro-angiogenic and anti-senescence factor in EPC-CM.
- MIF mimicked EPC-CM's therapeutic effects, which were blocked by MIF-specific antibodies.
- MIF promoted angiogenesis and anti-senescence by activating the AKT pathway, crucial for observed functional recovery.
Conclusions:
- EPC-CM protects against chronic ischemic brain injury and enhances functional recovery via MIF-mediated AKT pathway activation.
- EPC-CM represents a promising cell-free therapeutic for CCI, leveraging the actions of MIF.
Background:
Chronic cerebral ischemia (CCI) is a significant health issue characterized by hypoperfusion due to damage or occlusion of the cerebral or carotid arteries. CCI may lead to progressive cognitive impairment that is considered as a prelude to neurodegenerative diseases, including dementia and Alzheimer's disease (AD). Endothelial progenitor cells (EPCs) have been implicated in vascular repair in ischemic cerebrovascular diseases, primarily by differentiating into endothelial cells (ECs) or through paracrine effects. However, the clinical transplantation of stem cell therapies remains limited. In this study, we investigated the effects of EPC-derived conditioned medium (EPC-CM) on the impaired vasculature and neurological function in a rodent model of CCI and the mechanism involved.
Methods:
EPC-CM was analyzed by cytokine array to identify key factors involved in angiogenesis and cellular senescence. The effects and mechanism of the candidate factors in the EPC-CM were validated in vitro using oxygen-glucose deprivation (OGD)-injured ECs and EPCs. The therapeutic effects of EPC-CM and the identified key factor were further examined in a rat model of CCI, which was induced by bilateral internal carotid artery ligation (BICAL). EPC-CM was administered via intracisternal injection one week post BICAL. The cerebral microvasculature and neurobehavior of the rats were examined three weeks after BICAL.
Results:
Macrophage migration inhibitory factor (MIF) was identified as a key factor in the EPC-CM. Recombinant MIF protein promoted angiogenesis and prevented senescence in the injured EPCs and ECs. The effect was similar to that of the EPC-CM. These therapeutic effects were diminished when the EPC-CM was co-treated with MIF-specific antibody (Ab). Additionally, the vascular, motor, and cognitive improvements observed in the BICAL rats treated with EPC-CM were abolished by co-treated with MIF Ab. Furthermore, we found MIF promoted angiogenesis and anti-senescence via activating the AKT pathway. Inhibition of the AKT pathway diminished the protective effects of MIF in the in vitro study.
Conclusions:
We demonstrated that EPC-CM protected the brain from chronic ischemic injury and promoted functional recovery through MIF-mediated AKT pathway. These findings suggest EPC-CM holds potential as a novel cell-free therapeutic approach for treating CCI through the actions of MIF.
