Best D Hunter, Coleman William B
Department of Pathology and Laboratory Medicine, Curriculum in Toxicology, UNC Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Hepatology. 2007 Nov;46(5):1611-9. doi: 10.1002/hep.21876.
Liver regeneration after surgical partial hepatectomy (PH) in retrorsine-exposed rats is accomplished through the outgrowth and expansion of small hepatocyte-like progenitor cells (SHPCs). The cells of origin for SHPCs and their tissue niche have not been identified. Nevertheless, some investigators have suggested that SHPCs may represent an intermediate or transitional cell type between oval cells and mature hepatocytes, rather than a distinct progenitor cell population. We investigated this possibility through the targeted elimination of oval cell proliferation secondary to bile duct destruction in retrorsine-exposed rats treated with 4,4'-diaminodiphenylmethane (DAPM). Fischer 344 rats were treated with 2 doses (30 mg/kg body weight) retrorsine (at 6 and 8 weeks of age) followed by PH 5 weeks later. Twenty-four hours before PH, select animals were given a single dose of DAPM (50 mg/kg). Treatment of rats with DAPM produced severe bile duct damage but did not block liver regeneration. Oval cells were never seen in the livers of DAPM-treated retrorsine-exposed rats after PH. Rather, liver regeneration in these rats was mediated by the proliferation of SHPCs, and the cellular response was indistinguishable from that observed in retrorsine-exposed rats after PH. SHPC clusters emerge 1 to 3 days post-PH, expand through 21 days post-PH, with normalization of the liver occurring by the end of the experimental interval.
These results provide direct evidence that SHPC-mediated liver regeneration does not require oval cell activation or proliferation. In addition, these results provide strong evidence that SHPCs are not the progeny of oval cells but represent a distinct population of liver progenitor cells.
在经逆没食子酸处理的大鼠中，手术部分肝切除（PH）后的肝脏再生是通过小肝细胞样祖细胞（SHPCs）的生长和扩增来完成的。SHPCs的细胞起源及其组织微环境尚未确定。然而，一些研究人员认为，SHPCs可能代表卵圆细胞和成熟肝细胞之间的中间或过渡细胞类型，而不是一个独特的祖细胞群体。我们通过在经4,4'-二氨基二苯甲烷（DAPM）处理的逆没食子酸处理的大鼠中，靶向消除继发于胆管破坏的卵圆细胞增殖来研究这种可能性。将Fischer 344大鼠用2剂（30mg/kg体重）逆没食子酸（在6周和8周龄时）处理，然后在5周后进行PH。在PH前24小时，给选定的动物单次注射DAPM（50mg/kg）。用DAPM处理大鼠会导致严重的胆管损伤，但不会阻断肝脏再生。在PH后，在经DAPM处理的逆没食子酸处理的大鼠肝脏中从未见过卵圆细胞。相反，这些大鼠的肝脏再生是由SHPCs的增殖介导的，并且细胞反应与在PH后经逆没食子酸处理的大鼠中观察到的反应没有区别。SHPC簇在PH后1至3天出现，在PH后21天内扩增，在实验间隔结束时肝脏恢复正常。
这些结果提供了直接证据，表明SHPC介导的肝脏再生不需要卵圆细胞激活或增殖。此外，这些结果提供了有力证据，表明SHPCs不是卵圆细胞的后代，而是代表一个独特肝祖细胞群体。
