Endothelial progenitor cell-derived conditioned medium mitigates chronic cerebral ischemic injury through macrophage migration inhibitory factor-activated AKT pathway.

Autor: Cheng YW; Division of Neurosurgery, Department of Surgery, National Taiwan University Hospital, No.7, Chung-Shan South Road, Taipei, 100, Taiwan., Yang LY; Division of Neurosurgery, Department of Surgery, National Taiwan University Hospital, No.7, Chung-Shan South Road, Taipei, 100, Taiwan., Chen YT; Division of Neurosurgery, Department of Surgery, National Taiwan University Hospital, No.7, Chung-Shan South Road, Taipei, 100, Taiwan.; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan., Chou SC; Division of Neurosurgery, Department of Surgery, National Taiwan University Hospital, No.7, Chung-Shan South Road, Taipei, 100, Taiwan.; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan., Chen KW; Division of Neurosurgery, Department of Surgery, National Taiwan University Hospital, No.7, Chung-Shan South Road, Taipei, 100, Taiwan.; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan., Chen YH; Division of Neurosurgery, Department of Surgery, National Taiwan University Hospital, No.7, Chung-Shan South Road, Taipei, 100, Taiwan.; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan., Deng CR; Division of Neurosurgery, Department of Surgery, National Taiwan University Hospital, No.7, Chung-Shan South Road, Taipei, 100, Taiwan., Chen IC; Division of Neurosurgery, Department of Surgery, National Taiwan University Hospital, No.7, Chung-Shan South Road, Taipei, 100, Taiwan., Chou WJ; Division of Neurosurgery, Department of Surgery, National Taiwan University Hospital, No.7, Chung-Shan South Road, Taipei, 100, Taiwan.; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan., Chang CC; Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan., Chen YR; Non-Invasive Cancer Therapy Research Institute, Taipei, Taiwan.; Adjunct Visiting Staff, Division of Neurosurgery, Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan., Hwa HL; Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan., Wang KC; Division of Neurosurgery, Department of Surgery, National Taiwan University Hospital, No.7, Chung-Shan South Road, Taipei, 100, Taiwan. wang081466@yahoo.com.tw., Kuo MF; Division of Neurosurgery, Department of Surgery, National Taiwan University Hospital, No.7, Chung-Shan South Road, Taipei, 100, Taiwan. mfkenator@gmail.com.
Jazyk: angličtina
Zdroj: Stem cell research & therapy [Stem Cell Res Ther] 2024 Nov 14; Vol. 15 (1), pp. 428. Date of Electronic Publication: 2024 Nov 14.
DOI: 10.1186/s13287-024-04015-5
Abstrakt: 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.
Competing Interests: Declarations Ethics approval and consent to participate This animal experiments were conducted in accordance with the ARRIVE guidelines (Animal Research: Reporting of In Vivo Experiments) and was approved by the Institutional Animal Care and Use Committee of National Taiwan University (Approval no. IACUC-20180430, date of approval: 08/01/2019). The EPCs were collected from fresh human umbilical cord blood and was approved by the Institutional Review Board of National Taiwan University Hospital, Taipei, Taiwan (Study title: Platform establishment, validation, and biomarkers study in cerebrovascular diseases: using pediatric moyamoya disease as a pilot. Approval no. IRB-201204074RIC, date of approval: 07/04/2012; Study title: The pathophysiology of indirect revascularization in chronic cerebral ischemia-induced tauopathy: an in vitro, in vivo and clinical study. Approval no. IRB-202012174RIND, date of approval: 01/19/2021). All patients gave written informed consent for participation in the study and the use of samples. Consent for publication All the authors approved this manuscript to be published in the Journal Stem Cell Research & Therapy. Competing interests The authors declare no competing interests.
(© 2024. The Author(s).)
Databáze: MEDLINE
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