On the origin of the liver

Abstract

and colleagues (5) establishes a framework for how to tease out genetic and biochemical modifiers of complex phenotypes in monogenic disorders such as IBMPFD and neurofibromatosis type 1.

Hepatocellular carcinoma originates from hepatocytes and not from the progenitor/biliary compartment

“…This is consistent with the key role of the terminally differentiated hepatocyte in generating new hepatocytes in the normal and injured liver (8,14,(16)(17)(18). In view of the recently suggested hypothesis that the number of stem cell doublings determines cancer risk across various organs (50), the hepatocyte should be seen as a fully differentiated cell with stem cell-like functions that is at risk for malignant transformation with increasing numbers of doublings, similar to other stem cell populations.…”

“…In contrast to many organs that have a hierarchical organization depending on well-defined stem cell populations, such as intestine and skin (4)(5)(6), the fully differentiated hepatocyte is endowed with an almost infinite capacity to regenerate (7). Accordingly, regeneration following most types of injury or after partial hepatectomy is achieved from the hepatocyte pool without major contribution of progenitor cells (3,8). However, when liver injury is chronic and when the ability of mature hepatocytes to proliferate is blocked, a reserve cell compartment located within the biliary compartment -often termed oval cells or liver progenitor cells (LPCs) -expands in patients and in experimental injury models and may contribute to the formation of hepatocytes (3,7,(9)(10)(11)(12)(13).…”

“…However, when liver injury is chronic and when the ability of mature hepatocytes to proliferate is blocked, a reserve cell compartment located within the biliary compartment -often termed oval cells or liver progenitor cells (LPCs) -expands in patients and in experimental injury models and may contribute to the formation of hepatocytes (3,7,(9)(10)(11)(12)(13). However, several recent fate-tracing studies have challenged a major role for the LPC/ biliary compartment in the formation of hepatocytes, showing either no or only very little contribution to the hepatocyte pool (8,(14)(15)(16)(17)(18). On the other hand, the LPC/biliary compartment is capable of generating functional hepatocytes in zebrafish (19), indicating that its contribution may be model-, disease-, or species-specific.…”

Adult Hepatocytes Are Generated by Self-Duplication Rather than Stem Cell Differentiation

“…Based on in vitro studies, ultrastructural analyses, and cell transplantation assays, ADCs have been proposed to function as bipotent facultative stem cells, giving rise to both hepatocytes and BECs, during toxin-mediated liver injury, although this issue is controversial (Español-Suñer et al, 2012; Fausto and Campbell, 2003; Friedman and Kaestner, 2011; Furuyama et al, 2011; Huch et al, 2013; Malato et al, 2011; Zaret and Grompe, 2008). Furthermore, adult hepatocytes exhibit significant plasticity in vivo, a phenomenon that may give the appearance of stem-cell-mediated differentiation (Michalopoulos et al, 2005; Tanimizu et al, 2014; Yanger et al, 2013).…”

Spontaneous development of hepatocellular carcinoma with cancer stem cell properties in PR ‐ SET 7‐deficient livers

“…Notwithstanding, liver regeneration after most forms of acute injury or 2/3 rd partial hepatectomy does not rely on progenitor cell activation, but instead involves the proliferation of existing previously quiescent hepatocytes (Malato et al , 2011; Español-Suñer et al , 2012; Schaub et al , 2014; Yanger et al , 2014). Progenitor-dependent regeneration is probably restricted to chronic injury conditions coupled with impaired hepatocyte replication potential (Yamaji et al , 2010; Friedman & Kaestner, 2011; Wang et al , 2011; Miyajima et al , 2014). …”