Chemokine Ligand 5 (CCL5) Derived from Endothelial Colony-Forming Cells (ECFCs) Mediates Recruitment of Smooth Muscle Progenitor Cells (SPCs) toward Critical Vascular Locations in Moyamoya Disease

Abstract

The etiology and pathogenesis of moyamoya disease (MMD) are still obscure. Previous studies indicated that angiogenic chemokines may play an important role in the pathogenesis of the disease. Recently, it was discovered that peripheral blood-derived endothelial colony-forming cells (ECFCs) and smooth muscle progenitor cells (SPCs) have defective functions in MMD patients. Therefore, the interaction of ECFCs and SPCs, the precursors of two crucial cellular components of vascular walls, with some paracrine molecules is an intriguing subject. In this study, co-culture of ECFCs and SPCs from MMD patients and healthy normal subjects revealed that MMD ECFCs, not SPCs, are responsible for the defective functions of both ECFCs and SPCs. Enhanced migration of SPCs toward MMD ECFCs supported the role for some chemokines secreted by MMD ECFCs. Expression arrays of MMD and normal ECFCs suggested that several candidate cytokines differentially produced by MMD ECFCs. We selected chemokine (C-X-C motif) ligand 6 (CXCR6), interleukin-8 (IL8), chemokine (C-C motif) ligand 2 (CCL2), and CCL5 for study, based on the relatively higher expression of these ligands in MMD ECFCs and their cognate receptors in MMD SPCs. Migration assays showed that only CCL5 significantly augmented the migration activities of SPCs toward ECFCs. Treatment with siRNA for the CCL5 receptor (CCR5) abrogated the effect, confirming that CCL5 is responsible for the interaction of MMD ECFCs and SPCs. These data indicate that ECFCs, not SPCs, are the major players in MMD pathogenesis and that the chemokine CCL5 mediates the interactions. It can be hypothesized that in MMD patients, defective ECFCs direct aberrant SPC recruitment to critical vascular locations through the action of CCL5.

Circulating endothelial progenitor cells and endothelial cells in moyamoya disease

“…The most characteristic feature of MMD pathology is thickening of the intima with the proliferation of smooth muscle cells (Phi et al., 2017). The etiology of MMD remains unknown.…”

“…Moyamoya disease (MMD) is a progressive occlusive cerebrovascular disease of the internal carotid arteries or their branches with compensatory development of a fine collateral vascular network at the base of the brain (moyamoya vessels) (Suzuki & Takaku, 1969;Takeuchi & Shimizu, 1957). The most characteristic feature of MMD pathology is thickening of the intima with the proliferation of smooth muscle cells (Phi et al, 2017). The etiology of MMD remains unknown.…”

Pro-angiogenic effect of RANTES-loaded polysaccharide-based microparticles for a mouse ischemia therapy

“…The positive effects of RANTES to induce neo-angiogenesis and muscle regeneration may be of interest to restore blood flow to ischemic tissues after vessel occlusion. In addition to its effect on endothelial cells, RANTES also induces the recruitment of smooth muscle progenitor cells 50 . The mobilization of EPC from bone marrow to the blood flow, their migration to the site of ischemia, and their incorporation into neo-vessels are essential steps of limb tissue repair process 51 .…”

Impaired functional recovery of endothelial colony-forming cells from moyamoya disease in a chronic cerebral hypoperfusion rat model

“…In addition to the ECFC abnormalities, smooth muscle progenitor cells (SMPCs) and chemokines between the two cells are also thought to play a role in intimal thickening and proliferation of smooth muscle, which are characteristic of MMD. 19,25 Experiments on MMD SMPCs or other chemokines were not performed in this study, and these aspects need to be addressed in future studies. However, because it is believed that MMD ECFCs play a major role in the dysfunction of both ECFCs and SMPCs and the interaction between them, rather than MMD SMPCs, 25 it is important to provide a basis for future studies by identifying the functional abnormalities of MMD ECFCs in vivo using animal models.…”

“…19,25 Experiments on MMD SMPCs or other chemokines were not performed in this study, and these aspects need to be addressed in future studies. However, because it is believed that MMD ECFCs play a major role in the dysfunction of both ECFCs and SMPCs and the interaction between them, rather than MMD SMPCs, 25 it is important to provide a basis for future studies by identifying the functional abnormalities of MMD ECFCs in vivo using animal models. In our study we applied the 2-VO rat model, which is a suitable one for inferring the function of ECFCs in MMD, 3,7,34 and we first identified and verified the abnormal and decreased angiogenic potential of MMD ECFCs in this rat model.…”