Abo-Aziza Faten A M, Zaki Abdel Kader A, Adel Rana M, Fotouh Ahmed
Department of Parasitology and Animal Diseases, Veterinary Research Institute, National Research Centre, Cairo, Egypt.
Department of Physiology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt.
Vet World. 2022 May;15(5):1347-1364. doi: 10.14202/vetworld.2022.1347-1364. Epub 2022 May 27.
Bone marrow-derived mesenchymal stem cells (BM-MSCs) transplantation and their hepatogenic differentiated cells (HDCs) can be applied for liver injury repair by tissue grafting. Regenerative potentiality in liver cirrhosis models was widely investigated; however, immunomodulation and anti-inflammation in acute hepatitis remain unexplored. This study aimed to explore the immunomodulatory and evaluate twice intravenous (IV) or intrahepatic (IH) administration of either BM-MSCs or middle-stage HDCs on aflatoxin (AF) acute hepatitis rat model.
BM-MSCs viability, phenotypes, and proliferation were evaluated. Hepatogenic differentiation, albumin, and mmmmmmmm-fetoprotein gene expression were assessed. AF acute hepatitis was induced in rats using AFB1 supplementation. The transplantation of BM-MSCs or their HDCs was done either by IV or IH route. Hepatic ultrasound was performed after 3-weeks of therapy. Cytokines profile (tumor necrosis factor-α [TNF-α], interleukin [IL]-4, and IL-10) was assessed. Hepatic bio-indices, serum, and hepatic antioxidant activity were evaluated, besides examining liver histological sections.
Acute AFB1 showed a significant increase in TNF-α (p<0.01), liver enzyme activities (p<0.05), as well as decrease in IL-4, IL-10, and antioxidant enzyme activities (p<0.05). Cytokines profile was ameliorated in groups treated with IV and IH BM-MCs, showed a negative correlation between IL-4 and TNF-α (p<0.05), and a positive correlation between IL-10 upregulation and TNF-α (p<0.01). In IV HDCs treated group, positive correlations between IL-4 and IL-10 downregulation and TNF-α were observed. However, in IH HDCs group, a significant positive correlation between IL-4 and IL-10 upregulation and TNF-α, were recorded (p<0.05). In addition, IV BM-MSCs and IH HDCs treatments significantly increased antioxidant enzymes activity (p<0.05). IV and IH BM-MSCs significantly ameliorated liver transaminase levels, whereas IH HDCs significantly ameliorated alanine aminotransferase activity and nitric oxide concentration (p<0.05).
The administration routes of BM-MSCs did not demonstrate any significant difference; however, the IH route of HDCs showed significant amelioration from the IV route. On the other hand, it showed noticeable anti-inflammatory and immunomodulatory improvements in aflatoxicosis rats. Therefore, it can be concluded that acute hepatitis can be treated by a noninvasive IV route without the expense of hepatogenic differentiation. Further research using clinical trials that address several problems regarding engraftment and potentiation are needed to determine the optimal manipulation strategy as well as to achieve better long term effects.
骨髓间充质干细胞（BM-MSCs）移植及其肝源性分化细胞（HDCs）可通过组织移植用于肝损伤修复。肝硬化模型中的再生潜能已得到广泛研究；然而，急性肝炎中的免疫调节和抗炎作用仍未被探索。本研究旨在探讨免疫调节作用，并评估BM-MSCs或中期HDCs经静脉（IV）或肝内（IH）两次给药对黄曲霉毒素（AF）急性肝炎大鼠模型的影响。
评估BM-MSCs的活力、表型和增殖情况。评估肝源性分化、白蛋白和甲胎蛋白基因表达。通过补充AFB1诱导大鼠发生AF急性肝炎。BM-MSCs或其HDCs通过IV或IH途径进行移植。治疗3周后进行肝脏超声检查。评估细胞因子谱（肿瘤坏死因子-α [TNF-α]、白细胞介素 [IL]-4和IL-10）。除了检查肝脏组织切片外，还评估肝脏生物指标、血清和肝脏抗氧化活性。
急性AFB1使TNF-α显著升高（p<0.01）、肝酶活性升高（p<0.05），同时使IL-4、IL-10和抗氧化酶活性降低（p<0.05）。IV和IH BM-MSCs治疗组的细胞因子谱得到改善，IL-4与TNF-α呈负相关（p<0.05），IL-10上调与TNF-α呈正相关（p<0.01）。在IV HDCs治疗组中，观察到IL-4和IL-10下调与TNF-α呈正相关。然而，在IH HDCs组中，记录到IL-4和IL-10上调与TNF-α呈显著正相关（p<0.05）。此外，IV BM-MSCs和IH HDCs治疗显著提高了抗氧化酶活性（p<0.05）。IV和IH BM-MSCs显著改善了肝转氨酶水平，而IH HDCs显著改善了丙氨酸转氨酶活性和一氧化氮浓度（p<0.05）。
BM-MSCs的给药途径未显示出任何显著差异；然而，HDCs的IH途径与IV途径相比显示出显著改善。另一方面，它在黄曲霉毒素中毒大鼠中显示出明显的抗炎和免疫调节改善。因此，可以得出结论，急性肝炎可以通过无创的IV途径治疗，而无需进行肝源性分化。需要进一步开展临床试验研究，解决有关植入和增强作用的几个问题，以确定最佳操作策略并实现更好的长期效果。
