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血管内皮生长因子过表达的中胚层基质细胞增强了大鼠阴道模拟分娩后的尿道和阴道恢复。

VEGF overexpressed mesoangioblasts enhance urethral and vaginal recovery following simulated vaginal birth in rats.

机构信息

Group Biomedical Sciences, Centre for Surgical Technologies, KU Leuven, Leuven, Belgium.

Group Biomedical Sciences, Woman and Child, Department of Development and Regeneration, KU Leuven, Leuven, Belgium.

出版信息

Sci Rep. 2023 May 27;13(1):8622. doi: 10.1038/s41598-023-35809-x.

Abstract

Vaginal birth causes pelvic floor injury which may lead to urinary incontinence. Cell therapy has been proposed to assist in functional recovery. We aim to assess if intra-arterial injection of rat mesoangioblasts (MABs) and stable Vascular Endothelial Growth Factor (VEGF)-expressing MABs, improve recovery of urethral and vaginal function following simulated vaginal delivery (SVD). Female rats (n = 86) were assigned to either injection of saline (control), allogeneic-MABs (MABs), autologous-MABs (MABs) or allogeneic-MABs transduced to stably expressed VEGF (MABs). One hour after SVD, 0.5 × 10 MABs or saline were injected into the aorta. Primary outcome was urethral (7d and 14d) and vaginal (14d) function; others were bioluminescent imaging for cell tracking (1, 3 and 7d), morphometry (7, 14 and 60d) and mRNAseq (3 and 7d). All MABs injected rats had external urethral sphincter and vaginal function recovery within 14d, as compared to only half of saline controls. Functional recovery was paralleled by improved muscle regeneration and microvascularization. Recovery rate was not different between MABs and MABs. MABs accelerated functional recovery and increased GAP-43 expression at 7d. At 3d we detected major transcriptional changes in the urethra of both MABs and MABs-injected animals, with upregulation of Rho/GTPase activity, epigenetic factors and dendrite development. MABS also upregulated transcripts that encode proteins involved in myogenesis and downregulated pro-inflammatory processes. MABs also upregulated transcripts that encode proteins involved in neuron development and downregulated genes involved in hypoxia and oxidative stress. At 7d, urethras of MABs-injected rats showed downregulation of oxidative and inflammatory response compared to MABS. Intra-arterial injection of MABs enhances neuromuscular regeneration induced by untransduced MABs and accelerates the functional urethral and vaginal recovery after SVD.

摘要

阴道分娩会导致盆底损伤,进而导致尿失禁。细胞疗法已被提议用于辅助功能恢复。我们旨在评估经动脉注射大鼠中胚层血管母细胞(MAB)和稳定表达血管内皮生长因子(VEGF)的 MAB 是否能改善模拟阴道分娩(SVD)后尿道和阴道功能的恢复。将雌性大鼠(n=86)分为盐水(对照)、同种异体-MAB(MABs)、自体-MAB(MABs)或稳定表达 VEGF 的同种异体-MAB(MABs)注射组。SVD 后 1 小时,将 0.5×10 MAB 或生理盐水注射到主动脉中。主要结局是尿道(7d 和 14d)和阴道(14d)功能;其他结局是细胞示踪的生物发光成像(1、3 和 7d)、形态测量学(7、14 和 60d)和 mRNAseq(3 和 7d)。与生理盐水对照组相比,所有注射 MAB 的大鼠在 14d 内均恢复了尿道外括约肌和阴道功能,而只有一半的生理盐水对照组大鼠恢复了功能。功能恢复与肌肉再生和微血管化的改善相平行。MABs 和 MABs 的恢复速度没有差异。MABs 在 7d 时加速了功能恢复并增加了 GAP-43 的表达。在 3d 时,我们在 MABs 和 MABs 注射动物的尿道中都检测到了主要的转录变化,上调了 Rho/GTPase 活性、表观遗传因子和树突发育。MABS 还上调了编码肌生成蛋白的转录本,并下调了促炎过程。MABS 还上调了编码神经元发育蛋白的转录本,并下调了与缺氧和氧化应激相关的基因。在 7d 时,与 MABS 相比,MABs 注射大鼠的尿道下调了氧化和炎症反应。经动脉注射 MABs 可增强未转导的 MAB 诱导的神经肌肉再生,并加速 SVD 后尿道和阴道的功能恢复。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6020/10224946/426c686c5d9a/41598_2023_35809_Fig1_HTML.jpg

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