The mechanisms and applications of endothelial progenitor cell therapy in the treatment of intracranial aneurysm

Abstract

The pathophysiological mechanism of intracranial aneurysm (IA) involves the dynamic interaction of ECM abnormalities, hemodynamic stress, and inflammatory response. The rupture of intracranial aneurysm will cause serious consequences. Multiple studies have confirmed the important role and potential application of endothelial progenitor cells (EPCs) in vascular repair. This review focuses on the specific mechanism of EPCs in the treatment of intracranial aneurysms, which promote re-endothelialization and angiogenesis through bone marrow mobilization, targeted migration to the site of injury, differentiation into mature endothelial cells, and secretion of angiogenic factors. In addition, EPCs maintain ECM homeostasis by regulating MMP/IMP balance, inhibiting aneurysm wall thinning and structural damage. Based on the vascular repair mechanism of EPCs, new treatment strategies such as "biologically active" spring coils (loaded with EPCs or SDF-1α) and flow diverters(FDs) combined with EPCs therapy have been developed to synergistically promote carotid endothelialization of aneurysms and reduce the risk of recurrence. Future research needs to further validate the long-term efficacy and precise regulatory mechanisms of EPCs in clinical translation, providing new directions for IA treatment.

Keywords: Endothelial progenitor cell; Endothelialization; Endovascular treatment; Intracranial aneurysm.

Fig. 1

Two different types of EPC. Early EPCs Originating from bone marrow or hematopoietic progenitor cells, spindle shaped. Cultivation period: 4–7 days. Markers: CD14⁺/CD115⁺ (monocyte/macrophage characteristics), CD31/CD34/CD133/VEGFR-2/CD45⁺ (dual markers of endothelium and hematopoiesis). Function: Intake of Acetylated low-density lipoprotein and binding to UEA-1; Secreted high levels of VEGF/IL-8; Promotes angiogenesis but weak proliferative ability, making it difficult to propagate. Potential role: vascular repair and inflammation regulation. Late EPCs Source and morphology: Derived from bone marrow CD34 ⁺ hematopoietic stem cells, with a pebble like morphology. Cultivation period: 14–21 days. Markers: CD14 ⁻/CD115 ⁻, high expression of KDR/CXCR-1; Low hematopoietic related markers (WAS/LYN). Function: Strong proliferative ability, capable of forming capillary like structures; The in vitro angiogenic activity is comparable to eEPC. Characteristics: It is closer to mature endothelial cells and exhibits microvascular endothelial behavior

Fig. 2

Flow diverter and EPCs synergistically promote endothelialization. After stent implantation, inflammation of the vascular wall is triggered firstly, attracting inflammatory cells and a series of inflammatory factors are released including VEGF, FGF, SDF-1α, NO, CXCR-8, and Angiopoietin-1 these cytokines promote the proliferation and migration of EPCs toward the site of vascular damage. After the mobilization, the surface markers PSGL-1 and CD34 are combined with P-selectin and E-selectin accordingly. Then the EPC differentiate into endothelial cells along the scaffold, and a new endothelial layer is formed eventually. The damaged endothelial cells also release some cytokines like VEGF, SDF-1α, GM-CSF, which can activate MMP-9, then trigger the combination of SKITL and c-Kit that enhance the proliferation and mobilization of EPCs