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Human tri-layer engineered blood vessel reveals influence of fibroblasts on disease progression in model of Hutchinson-Gilford Progeria Syndrome

ABSTRACT: To date, in vitro models of vascular disease have focused on the pathophysiology of smooth muscle (SMC) or endothelial (EC) cells. Adventitial fibroblasts can contribute to disease progression, but their specific influence is not well understood in different disease contexts. To elucidate fibroblast’s impact on vascular pathology, we developed patient-specific, tri-layer tissue-engineered blood vessels (TEBVs) with SMCs, ECs, and fibroblasts. Using bi-layer (SMCs and ECs) and tri-layer TEBVs, we modeled atherosclerosis in the accelerated aging disease, Hutchinson-Gilford Progeria Syndrome (HGPS). HGPS fibroblasts substantially elevated several features of the vascular pathology. Correcting the HGPS-associated mutation using base editing returned many disease characteristics to healthy levels. By generating TEBVs with different combinations of vascular cells with or without the HGPS mutation, we found that fibroblasts contributed to ECM dysregulation and fibrotic signaling, SMCs to collagen accumulation and calcification, and ECs to inflammation. These results clarify the poorly understood influence of fibroblasts in the progression of HGPS vascular pathology. The tri-layer TEBV model could enable further mechanistic insights or therapeutic discovery for other vascular diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE333565 | GEO | 2026/09/01

REPOSITORIES: GEO

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Project description:Coronary artery disease is the leading cause of mortality in women. Abnormal growth of smooth muscle cells and endothelial damage contributes to the thickening of the blood vessels and vascular occlusion. Estradiol prevents vascular remodleing by promoting EC growth and inhibiting SMC growth. Recent studies suggest that circulating (bone marrow derived) progenitor cells also contribute to the vascular remodeling process. Whether estradiol could, in part, induce its protective actions by inhibiting P-SMC growth remains unknown. In this study, progenitor smooth muscle cells (P-SMCs) and endothelial (P-ECs) grown from CD34+ progenitor cells (PC) magnetically separated from human cord blood derived mononuclear cells. P-SMC and P-EC cell colonies were grown and characterized for SMC and EC markers. Cultured cells were further used to assess the effects of 17β-estradiol (E2; 10nM) on their growth and gene expression. Briefly, P-SMCs or P-ECs were treated with or without 10 nM E2 for 0, 4 or 30 hours in DMEM-F12 supplemented with 2.5% FCS (steroid-free; SF). Subsequently, total RNA was extracted using RNeasy Mini Kit (QIAGEN) processed for gene analysis. Treatment of P-SMCs with E2 inhibited 2.5% SF-serum -induced growth (DNA synthesis and cell number), whereas, E2 induced cell growth in P-ECs. The growth effects of E2 in P-SMCs and P-ECs were mimicked by ER-α agonist and blocked by ER-α antagonist. The differential effects of E2 on P-SMC and P-EC growth were also reflected in ERK1/2 and Akt phosphorylation and in positive and negative regulators of cell cycle. Gene analysis revealed that P-SMCs expressed SMC alpha actin (ACTA2) where as P-ECs expressed CD34, FLT1 and vWF, confirming the differentiation of progenitor cells to SMCs and ECs. Treatment with E2 for 30 hours regulated 1791 in P-SMCs and 220 in P-ECs, with 36 that were common. Volcano analysis showed that treatment with E2 for 30 hours differentially expressed multiple genes, importantly, estradiol significantly upregulated antimitogenic pathways and downregulated proproliferative pathways in P-SMC and P-ECs, respectively. Contrasting effects of E2 were also observed in multiple ingenuity canonical pathways that were up or downregulated in P-SMCs and P-ECs. Findings from both growth and gene expression studies provide evidence that etradiol may induce its vascular protective actions by inhibiting P-SMC activity and improving P-EC activity. Interestingly, in perpheral blood estradiol decreasd the number of c-kit+ cells and increased CD34+ cells. Since these cells evolve into SMCs and ECs respectively, our findings provide evidence that estradiol may induce its anti-occlusive actions by differentially regulating P-SMC and P-EC activity and numbers.

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Human tri-layer engineered blood vessel reveals influence of fibroblasts on disease progression in model of Hutchinson-Gilford Progeria Syndrome

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