The progenitor cell dilemma: Cellular and functional heterogeneity in assistance or escalation of liver injury

Abstract

Liver progenitor cells (LPCs) are quiescent cells that are activated during liver injury and thought to give rise to hepatocytes and cholangiocytes in order to support liver regeneration and tissue restitution. While hepatocytes are capable of self-renewal, during most chronic injuries the proliferative capacity of hepatocytes is inhibited, thus LPCs provide main source for regeneration. Despite extensive lineage tracing studies, their role and involvement in these processes are often controversial. Additionally, increasing evidence suggests that the LPC compartment consists of heterogeneous cell populations that are actively involved in cellular interactions with myeloid and lymphoid cells during regeneration. On the other hand, LPC expansion has been associated with an increased fibrogenic response, raising concerns about the therapeutic use of these cells. This review aims to summarize the current understanding of the identity, the cellular interactions and the key pathways affecting the biology of LPCs. Understanding the regulatory circuits and the specific role of LPCs is especially important as it could provide novel therapeutic platforms for the treatment of liver inflammation, fibrosis and regeneration. Ó

Interleukins‐17 and 27 promote liver regeneration by sequentially inducing progenitor cell expansion and differentiation

“…This suggests that IL‐17 could contribute to LPC expansion by i) directly promoting LPC proliferation and ii) indirectly through M1‐macrophage‐induced production of required factors, e.g., TNF‐α and IL‐6, which support LPC accumulation . IL‐17 has been detected in several types of chronic liver diseases and was associated with increased liver injury and fibrosis and hepatocellular carcinoma . Our data highlight that a sustained IL‐17 inflammatory response lacking a differentiating process may be responsible for incomplete hepatic regeneration, with uncontrolled accumulation of progenitor cells susceptible to undergo genetic and epigenetic alterations and to initiate carcinogenic processes.…”

Stem cells under the influence of alcohol: effects of ethanol consumption on stem/progenitor cells

“…Reduction of the capacity of the hepatocytes to replace damaged tissue parallels the induction of proliferation of the hepatic stem cells located in the Canals of Hering. This phenomenon, referred as ductular reaction, has been linked to alcohol hepatitis progression and severity [41], increased pro-fibrogenic response and tumor development [42]. …”

Myofibroblast induces hepatocyte-to-ductal metaplasia via laminin–ɑvβ6 integrin in liver fibrosis

“…The liver is a highly regenerative organ with the ability to restore its function after acute injury and chronic injury [1][2][3][4] . The cellular sources of regenerative hepatocytes in liver injury is a fundamental issue in liver biology [3][4][5][6][7][8] . In response to acute injury or loss of liver mass, remaining healthy liver cells proliferate to restore their functions 4,9 .…”

“…Stem-cell populations are established in niches or specific anatomic locations which maintain and regulate stem cell homeostasis. LPC niche is composed of hepatic stellate cells (HSCs), endothelial cells, macrophages, other inflammatory cells, extracellular matrix (ECM), growth factors, and cytokines 8,18,19 . HSCs, also known as Ito cells, are located in the space of Disse.…”