Human placental-derived stem cell therapy ameliorates experimental necrotizing enterocolitis
Human placental-derived stem cell therapy ameliorates experimental necrotizing enterocolitis
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人胎盘干细胞疗法可改善实验性坏死性小肠结肠炎
DOI：
10.1152/ajpgi.00369.2020
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发表时间：
2021
影响因子：
4.5
通讯作者：
Atala, Anthony
中科院分区：
文献类型：
--
作者：
Weis, Victoria G.;Deal, Anna C.;Mekkey, Gehad;Clouse, Cara;Gaffley, Michaela;Whitaker, Emily;Peeler, Cole B.;Weis, Jared A.;Schwartz, Marshall Z.;Atala, Anthony
坏死性小肠结肠炎 (NEC) 是一种危及生命的肠道疾病，正在成为早产儿发病和死亡的一个较大原因。迄今为止，治疗选择仍然难以捉摸。基于最近的细胞治疗研究，我们在实验性 NEC 幼鼠模型中研究了人胎盘源干细胞 (hPSC) 疗法对肠道损伤的影响。通过配方奶喂养、缺氧和 LPS 在新生 Sprague-Dawley 幼鼠中诱导 NEC 4 天。 NEC 幼崽在 NEC 诱导后 32 小时和 56 小时接受腹腔 (ip) 注射盐水或 hPSC (NEC-hPSC)。第4天，评估肠道宏观和组织学损伤、上皮细胞组成和回肠炎症标志物表达。母乳喂养（BF）同窝仔猪用作对照。 NEC 幼犬出现明显的肠扩张和回肠脆弱。此外，NEC 诱导正常绒毛隐窝形态的丧失、上皮增殖和细胞凋亡的破坏以及隐窝中关键祖细胞/干细胞和潘氏细胞群的丧失。 hPSC 治疗改善了宏观肠道健康，减少了回肠扩张和脆弱性。组织学上，hPSC 给药对绒毛隐窝形态和上皮具有显着的修复作用。除了炎症标志物表达减少的趋势外，与 NEC 同窝仔鼠相比，hPSC-NEC 幼仔的上皮增殖增加，细胞凋亡减少。此外，包括潘氏细胞、SOX9+细胞和LGR5+干细胞在内的肠道干细胞和隐窝微环境通过hPSC治疗得以恢复。总之，这些数据表明 hPSC 可以促进 NEC 肠道损伤的上皮愈合。新的和值得注意的这些研究证明了坏死性小肠结肠炎 (NEC) 的人胎盘源干细胞 (hPSC) 治疗策略。在 NEC 实验模型中，hPSC 给药改善了宏观肠道健康，改善了上皮形态，并支持肠道干细胞生态位。我们的数据表明 hPSC 是减轻肠道 NEC 损伤的潜在治疗方法。此外，我们表明 hPSC 是一种新型研究工具，可用于阐明克服 NEC 的关键新生儿修复机制。
Necrotizing enterocolitis (NEC), a life-threatening intestinal disease, is becoming a larger proportionate cause of morbidity and mortality in premature infants. To date, therapeutic options remain elusive. Based on recent cell therapy studies, we investigated the effect of a human placental-derived stem cell (hPSC) therapy on intestinal damage in an experimental NEC rat pup model. NEC was induced in newborn Sprague-Dawley rat pups for 4 days via formula feeding, hypoxia, and LPS. NEC pups received intraperitoneal (ip) injections of either saline or hPSC (NEC-hPSC) at 32 and 56 h into NEC induction. At 4 days, intestinal macroscopic and histological damage, epithelial cell composition, and inflammatory marker expression of the ileum were assessed. Breastfed (BF) littermates were used as controls. NEC pups developed significant bowel dilation and fragility in the ileum. Further, NEC induced loss of normal villi-crypt morphology, disruption of epithelial proliferation and apoptosis, and loss of critical progenitor/stem cell and Paneth cell populations in the crypt. hPSC treatment improved macroscopic intestinal health with reduced ileal dilation and fragility. Histologically, hPSC administration had a significant reparative effect on the villi-crypt morphology and epithelium. In addition to a trend of decreased inflammatory marker expression, hPSC-NEC pups had increased epithelial proliferation and decreased apoptosis when compared with NEC littermates. Further, the intestinal stem cell and crypt niche that include Paneth cells, SOX9+cells, and LGR5+stem cells were restored with hPSC therapy. Together, these data demonstrate hPSC can promote epithelial healing of NEC intestinal damage.NEW & NOTEWORTHYThese studies demonstrate a human placental-derived stem cell (hPSC) therapeutic strategy for necrotizing enterocolitis (NEC). In an experimental model of NEC, hPSC administration improved macroscopic intestinal health, ameliorated epithelial morphology, and supported the intestinal stem cell niche. Our data suggest that hPSC are a potential therapeutic approach to attenuate established intestinal NEC damage. Further, we show hPSC are a novel research tool that can be utilized to elucidate critical neonatal repair mechanisms to overcome NEC.