Sierra Romina, Gómez Bustillo Sofía, Kameneva Polina, Fiore Esteban J, Mazzone Graciela L, Borda Maximiliano, Blanco María V, Usuardi Chiara, Furlan Alessandro, Ernfors Patrik, Alaniz Laura, Montaner Alejandro D, Adameyko Igor, Aquino Jorge B
Developmental Biology and Regenerative Medicine Lab, IIMT CONICET-Universidad Austral, Pilar, Buenos Aires, Argentina.
Instituto de Ciencia y Tecnología Dr. César Milstein, Fundación Pablo Cassará, Buenos Aires, Argentina.
Liver Int. 2020 Apr;40(4):977-987. doi: 10.1111/liv.14401. Epub 2020 Feb 21.
Liver fibrosis results from cycles of liver damage and scar formation. We herein aimed at analysing neural crest cells and/or bone marrow stromal cells contribution to the liver.
Two liver fibrosis and one hepatectomy model were applied on double-transgenic loxP-Cre mouse lines.
Increased numbers of glia with more complex processes were found in fibrotic livers. During embryonic development, only few cells were traced in the liver and bone marrow, in a minor fraction of mice of different neural crest reporter strains analysed: therefore, a neural crest origin of such cells is doubtful. In the fibrotic liver, a significantly higher incidence of endothelial cells and hepatocyte-like cells expressing the reporter gene Tomato were found in Wnt1-Cre-Tom and GLAST-CreERT2-Tom mice. Consistently, during early fibrogenesis stromal Wnt1-traced cells, with progenitor (CFU-F) properties, get likely mobilized to peripheral blood. Circulating adult Wnt1-traced cells are stromal cells and lack from the expression of other bone marrow and endothelial progenitor cells markers. Furthermore, in a 70% hepatectomy model GLAST Wnt1-traced pericytes were found to be mobilized from the bone marrow and the incidence of GLAST-traced hepatocyte-like cells was increased. Finally, GLAST-traced hepatocyte like-cells were found to maintain the expression of stromal markers.
Our data suggest a gliosis process during liver fibrogenesis. While neural crest cells probably do not contribute with other liver cell types than glia, GLAST Wnt1-traced bone marrow pericytes are likely a source of endothelial and hepatocyte-like cells after liver injury and do not contribute to scarring.
肝纤维化源于肝损伤和瘢痕形成的循环过程。我们在此旨在分析神经嵴细胞和/或骨髓基质细胞对肝脏的贡献。
在双转基因loxP-Cre小鼠品系上应用两种肝纤维化模型和一种肝切除模型。
在纤维化肝脏中发现胶质细胞数量增加且细胞突起更复杂。在胚胎发育过程中，在分析的不同神经嵴报告基因品系的一小部分小鼠的肝脏和骨髓中仅追踪到少数细胞；因此，这些细胞的神经嵴起源值得怀疑。在纤维化肝脏中，在Wnt1-Cre-Tom和GLAST-CreERT2-Tom小鼠中发现表达报告基因Tomato的内皮细胞和肝细胞样细胞的发生率显著更高。一致地，在早期纤维化形成过程中，具有祖细胞（CFU-F）特性的基质Wnt1追踪细胞可能被动员到外周血中。循环中的成年Wnt1追踪细胞是基质细胞，缺乏其他骨髓和内皮祖细胞标志物的表达。此外，在70%肝切除模型中，发现GLAST Wnt1追踪的周细胞从骨髓中被动员出来，并且GLAST追踪的肝细胞样细胞的发生率增加。最后，发现GLAST追踪的肝细胞样细胞维持基质标志物的表达。
我们的数据表明肝纤维化形成过程中存在胶质细胞增生过程。虽然神经嵴细胞可能除了胶质细胞外不参与其他肝细胞类型的形成，但GLAST Wnt1追踪的骨髓周细胞可能是肝损伤后内皮细胞和肝细胞样细胞的来源，且不参与瘢痕形成。
