Bone Morphogenetic Protein-4 Modulates Proliferation and Terminal Differentiation of Fetal Hepatic Stem/Progenitor Cells.
Bone Morphogenetic Protein-4 Modulates Proliferation and Terminal Differentiation of Fetal Hepatic Stem/Progenitor Cells.
复制标题
骨形态发生蛋白 4 调节胎儿肝干细胞/祖细胞的增殖和终末分化。
DOI：
10.1111/hepr.12823
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发表时间：
2016
期刊：
影响因子：
4.2
通讯作者：
Watanabe M.
中科院分区：
文献类型：
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作者：
Goto F;Kakinuma S;Miyoshi M;Tsunoda T;Kaneko S;Sato A;Asano Y;Otani S;Azuma S;Nagata H;Kawai-Kitahata F;Murakawa M;Nitta S;Itsui Y;Nakagawa M;Asahina Y;Watanabe M.
目的胎儿肝干/祖细胞，称为成肝细胞，在肝脏器官发生中发挥核心作用；然而，调节此类细胞增殖和终末分化的分子机制尚未完全阐明。骨形态发生蛋白-4（BMP-4）对于各种组织干细胞的发育至关重要，但其在妊娠中期胎儿阶段后调节成肝细胞表型的功能仍不清楚。本研究的目的是阐明BMP-4在妊娠中期胎儿肝脏中小鼠成肝细胞增殖和终末分化中的功能作用。方法通过体外原代成肝细胞集落形成、胆管腔形成和肝成熟测定来验证BMP-4在小鼠成肝细胞增殖和终末分化中的功能作用。还分析了调节BMP-4对原代成肝细胞影响的分子机制。结果刺激BMP-4上调成肝细胞中Smad1/5的磷酸化。骨形态发生蛋白-4以剂量依赖性方式显着抑制原代成肝细胞集落形成，显着抑制成肝细胞胆管细胞腔形成，促进原代成肝细胞的肝脏成熟。 BMP-4 的刺激调节了原代成肝细胞中几种丝裂原激活蛋白激酶的激活，例如细胞外信号调节激酶、Akt、p38 丝裂原激活蛋白激酶和钙/钙调蛋白依赖性蛋白激酶 IIα。此外，调节胆管细胞腔形成的分子Wnt5a和BMP-4协同抑制成肝细胞的增殖和胆管细胞腔形成。结论本研究表明BMP-4介导的信号传导控制胎儿肝干/祖细胞的增殖和终末分化。
AimFetal hepatic stem/progenitor cells, called hepatoblasts, play central roles in liver organogenesis; however, molecular mechanisms regulating proliferation and terminal differentiation of such cells have not been completely elucidated. Bone morphogenetic protein‐4 (BMP‐4) is essential for the development of stem cells in various tissues, but its function in regulating the phenotype of hepatoblasts after the mid‐gestational fetal stage remains unclear. The aim of this study is to clarify a functional role for BMP‐4 in proliferation and terminal differentiation of murine hepatoblasts in mid‐gestational fetal livers.MethodsA functional role for BMP‐4 in proliferation and terminal differentiation of murine hepatoblasts was validated by assay of colony formation, biliary luminal formation, and hepatic maturation using primary hepatoblastsin vitro. Molecular mechanisms regulating such effects of BMP‐4 on primary hepatoblasts were also analyzed.ResultsStimulation of BMP‐4 upregulated phosphorylation of Smad1/5 in hepatoblasts. Bone morphogenetic protein‐4 significantly suppressed colony formation of primary hepatoblasts in a dose‐dependent manner, significantly suppressed cholangiocytic luminal formation of hepatoblasts, and promoted hepatic maturation of primary hepatoblasts. Stimulation of BMP‐4 regulated the activation of several mitogen‐activated protein kinases, such as extracellular signal‐regulated kinase, Akt, p38 mitogen‐activated protein kinase, and calcium/calmodulin‐dependent protein kinase IIα in primary hepatoblasts. Moreover, Wnt5a, a molecule regulating cholangiocytic luminal formation, and BMP‐4 coordinately suppressed proliferation and cholangiocytic luminal formation of hepatoblasts.ConclusionThis study shows that BMP‐4‐mediated signaling controls proliferation and terminal differentiation of fetal hepatic stem/progenitor cells.