Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, 12901 Bruce B Downs Blvd, Tampa, FL 33612, USA.
Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
Int J Mol Sci. 2023 Jun 25;24(13):10600. doi: 10.3390/ijms241310600.
Accumulating evidence suggests the critical role of the gut-brain axis (GBA) in Parkinson's disease (PD) pathology and treatment. Recently, stem cell transplantation in transgenic PD mice further implicated the GBA's contribution to the therapeutic effects of transplanted stem cells. In particular, intravenous transplantation of human umbilical-cord-blood-derived stem/progenitor cells and plasma reduced motor deficits, improved nigral dopaminergic neuronal survival, and dampened α-synuclein and inflammatory-relevant microbiota and cytokines in both the gut and brain of mouse and rat PD models. That the gut robustly responded to intravenously transplanted stem cells and prompted us to examine in the present study whether direct cell implantation into the gut of transgenic PD mice would enhance the therapeutic effects of stem cells. Contrary to our hypothesis, results revealed that intragut transplantation of stem cells exacerbated motor and gut motility deficits that corresponded with the aggravated expression of inflammatory microbiota, cytokines, and α-synuclein in both the gut and brain of transgenic PD mice. These results suggest that, while the GBA stands as a major source of inflammation in PD, targeting the gut directly for stem cell transplantation may not improve, but may even worsen, functional outcomes, likely due to the invasive approach exacerbating the already inflamed gut. The minimally invasive intravenous transplantation, which likely avoided worsening the inflammatory response of the gut, appears to be a more optimal cell delivery route to ameliorate PD symptoms.
越来越多的证据表明，肠道-大脑轴（GBA）在帕金森病（PD）的病理和治疗中起着关键作用。最近，在转基因 PD 小鼠中的干细胞移植进一步表明 GBA 有助于移植的干细胞的治疗效果。特别是，静脉内移植人脐血源性干细胞/祖细胞和血浆可减少运动缺陷，提高黑质多巴胺能神经元的存活，并抑制肠道和大脑中α-突触核蛋白和炎症相关的微生物群和细胞因子在小鼠和大鼠 PD 模型中。肠道对静脉内移植的干细胞有强烈的反应，这促使我们在本研究中检查直接将干细胞植入转基因 PD 小鼠的肠道是否会增强干细胞的治疗效果。与我们的假设相反，结果表明，干细胞的肠内移植加剧了运动和肠道运动缺陷，与转基因 PD 小鼠的肠道和大脑中炎症微生物群、细胞因子和α-突触核蛋白的表达加剧相对应。这些结果表明，虽然 GBA 是 PD 中炎症的主要来源，但直接针对肠道进行干细胞移植可能不会改善，甚至可能恶化功能结果，这可能是由于侵袭性方法加重了已经发炎的肠道。微创的静脉内移植可能避免了肠道炎症反应的恶化，似乎是一种更优化的细胞输送途径，可以改善 PD 症状。
