Stem cell factor and c-kit are involved in hepatic recovery after acetaminophen-induced liver injury in mice
Stem cell factor and c-kit are involved in hepatic recovery after acetaminophen-induced liver injury in mice
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DOI：
10.1152/ajpgi.00024.2008
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发表时间：
2008-07-01
影响因子：
4.5
通讯作者：
Colletti, Lisa M.
中科院分区：
文献类型：
--
作者：
Hu, Bin;Colletti, Lisa M.
干细胞因子(SCF)及其受体c-kit在造血和细胞增殖中起重要作用。C-KIT也被确定为祖细胞的细胞表面标志。我们之前已经证明，肝脏中有大量的干细胞因子，这种分子在70%肝切除术后的肝脏再生中发挥着重要作用。在本研究中，我们进一步检测了SCF和c-kit在对乙酰氨基酚(APAP)诱导的C57BL/6J小鼠和SCF缺陷的S1-SLD小鼠以及它们相应的野生型对照小鼠肝损伤中的表达。在APAP诱导的肝损伤后，c-kit mRNA表达增加，在损伤后48h达到高峰。APAP损伤后肝组织SCF基因表达水平也明显升高，在APAP后16h达高峰。APAP治疗的SCF缺陷小鼠的死亡率显著高于野生型小鼠；此外，外源性SCF的注射显著降低了APAP治疗的野生型小鼠的死亡率。溴脱氧尿嘧啶核苷掺入实验表明，SCF在48h和72h显著促进APAP处理的小鼠肝细胞的增殖。SCF可抑制APAP诱导的肝细胞凋亡，增加Bc1-2和Bc1-xl的表达，提示这种减少肝细胞凋亡的作用是通过Bc1-2和Bc1-xl介导的。综上所述，APAP诱导的肝损伤后，SCF和c-kit表达增加。应用外源性SCF可降低APAP处理小鼠的死亡率，促进肝细胞增殖，并防止APAP诱导的肝细胞凋亡，提示这些分子在肝脏从这些损伤中恢复是重要的。
Stem cell factor ( SCF) and its receptor c-kit are important in hematopoiesis and cellular proliferation. c-kit has also been identified as a cell surface marker for progenitor cells. We have previously shown that there is a large reservoir of hepatic SCF, and this molecule plays a significant role in liver regeneration after 70% hepatectomy. In the current study, we further examined the expression of SCF and c-kit in acetaminophen ( APAP)-induced liver injury in C57BL/6J mice or SCF-deficient s1-sld mice and their appropriate wild-type controls. Following APAP-induced liver injury, c-kit mRNA expression increased, with peak levels detected 48 h postinjury. Hepatic SCF mRNA levels after APAP injury were also increased, with peak levels seen 16 h post-APAP. The mortality rate in SCF-deficient mice treated with APAP was significantly higher than that of wild-type mice; furthermore, administration of exogenous SCF significantly reduced the mortality of APAP-treated wild-type mice. Bromodeoxyuridine incorporation experiments showed that SCF significantly increased hepatocyte proliferation at 48 and 72 h in APAP-treated mice. SCF inhibited APAP-induced hepatocyte apoptosis and increased Bcl-2 and Bc1-xL expression, suggesting that this decrease in hepatocyte apoptosis is mediated through Bc1-2 and Bc1-xL. In summary, SCF and c-kit expression was increased after APAP-induced liver injury. Administration of exogenous SCF reduces mortality in APAP-treated mice, increases hepatocyte proliferation, and prevents hepatocyte apoptosis induced by APAP, suggesting that these molecules are important in the liver's recovery from these injuries.