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Cellular and Molecular Basis of Liver Development

Donghun Shin, Satdarshan Pal Singh Monga

10.1002/cphy.c120022

Source: Volume 3, Issue 2, April 2013

Published online: April 2013

Full Article on Wiley Online Library



Abstract

Liver is a prime organ responsible for synthesis, metabolism, and detoxification. The organ is endodermal in origin and its development is regulated by temporal, complex, and finely balanced cellular and molecular interactions that dictate its origin, growth, and maturation. We discuss the relevance of endoderm patterning, which truly is the first step toward mapping of domains that will give rise to specific organs. Once foregut patterning is completed, certain cells within the foregut endoderm gain competence in the form of expression of certain transcription factors that allow them to respond to certain inductive signals. Hepatic specification is then a result of such inductive signals, which often emanate from the surrounding mesenchyme. During hepatic specification bipotential hepatic stem cells or hepatoblasts become apparent and undergo expansion, which results in a visible liver primordium during the stage of hepatic morphogenesis. Hepatoblasts next differentiate into either hepatocytes or cholangiocytes. The expansion and differentiation is regulated by cellular and molecular interactions between hepatoblasts and mesenchymal cells including sinusoidal endothelial cells, stellate cells, and also innate hematopoietic elements. Further maturation of hepatocytes and cholangiocytes continues during late hepatic development as a function of various growth factors. At this time, liver gains architectural novelty in the form of zonality and at cellular level acquires polarity. A comprehensive elucidation of such finely tuned developmental cues have been the basis of transdifferentiation of various types of stem cells to hepatocyte‐like cells for purposes of understanding health and disease and for therapeutic applications. © 2013 American Physiological Society. Compr Physiol 3:799‐815, 2013.

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Figure 1. Figure 1.

Diagrams depicting hepatic competence and liver specification. Once the endoderm is properly patterned anteroposteriorly, the foregut and midgut endoderm possess hepatic competence, shown here by FOXA1/2 and GATA4/6 expression (gray). Endodermal cells in the foregut endoderm receive hepatic inducing signals, bone morphogenic protein (BMP), fibroblast growth factor (FGF), and Wnt, from adjacent mesodermal tissues (green), and subsequently give rise to hepatoblasts (red).
Figure 2. Figure 2.

Diagrams of zebrafish early liver development. bmp2b is expressed in the lateral plate mesoderm (LPM) from 14 h postfertilization (hpf), and appears to suppress Pdx1 expression (green) in the neighboring endodermal cells (22). Some of these Pdx1− endodermal cells give rise to hepatoblasts. wnt2bb is expressed in the LPM from 18 hpf (dark blue) (102); the early hepatoblast marker Prox1 starts to be expressed in endodermal cells (red) anterior to the Pdx1+ domain from 24 hpf and is continuously expressed in the liver (L) (35). fgf10a is expressed in the LPM surrounding the Pdx1+ domain from 30 hpf (orange), and appears to repress hepatic competence (123). Ventral views of the endoderm and endoderm‐derived organs, anterior up.
Figure 3. Figure 3.

Representation of hepatic morphogenesis. Hepatoblasts, which are the hepatic progenitors, undergo expansion via balanced cell proliferation and survival. These bipotential stem cells then differentiate into hepatocytes or cholangiocytes (biliary epithelial cells). As the morphogenesis continues, these cells undergo maturation by acquiring additional characteristics such as polarity and now are primed to perform key cellular functions of the liver.
Figure 4. Figure 4.

Cellular and molecular basis of hepatoblast expansion. Various mesenchymal elements including endothelial cells, hepatic stellate cells and even hematopoietic stem cells (HSCs) are a source of key growth factors that act via paracrine mechanisms to induce proliferation of hepatoblasts that expresses receptors as well as key downstream effectors of these signaling mechanisms. Abbreviations: HGF‐hepatocyte growth factor; FGF(R)‐fibroblast growth factor (receptor); BMP(R)‐bone morphogenic protein (receptor); RAR‐retinoic acid receptor; JNK‐JUN NH2‐terminal kinase; PI3K‐phosphoinositide 3‐kinase; MAPK‐mitogen activated protein kinase.
Figure 5. Figure 5.

Molecular basis of cholangiocyte differentiation and maturation. Various instructive signals, either paracrine or autocrine, stimulate specification of cholangiocytes from the hepatoblasts and these signals induce specific transcription factor programs within the cholangiocytes. Once these cells are specified, they continue to respond to various growth factors, again in an autocrine or paracrine fashion, to mature and organize as ductal structures with specific functions. Abbreviations: TGFβ‐transforming growth factor β; HGF‐hepatocyte growth factor; FGF‐fibroblast growth factor; BMP‐bone morphogenic protein.
Figure 6. Figure 6.

Molecular basis of hepatocyte differentiation and maturation. Various instructive signals, either paracrine or autocrine, stimulate specification of hepatocytes from the hepatoblasts and these signals induce specific transcription factor programs within the hepatocytes. Once these cells are specified, they continue to respond to various growth factors, again in an autocrine or paracrine fashion, to mature, acquire cell polarity and gain expression of genes to enable specific functions.
Figure 7. Figure 7.

Diagrams depicting hepatocyte differentiation from embryonic stem (ES) or induced pluripotent stem (iPS) cells and the direct reprogramming of fibroblasts. Exogenous factors that induce differentiation are written in red; transcription factors that are required for fibroblast reprogramming are written in blue.


Figure 1.

Diagrams depicting hepatic competence and liver specification. Once the endoderm is properly patterned anteroposteriorly, the foregut and midgut endoderm possess hepatic competence, shown here by FOXA1/2 and GATA4/6 expression (gray). Endodermal cells in the foregut endoderm receive hepatic inducing signals, bone morphogenic protein (BMP), fibroblast growth factor (FGF), and Wnt, from adjacent mesodermal tissues (green), and subsequently give rise to hepatoblasts (red).



Figure 2.

Diagrams of zebrafish early liver development. bmp2b is expressed in the lateral plate mesoderm (LPM) from 14 h postfertilization (hpf), and appears to suppress Pdx1 expression (green) in the neighboring endodermal cells (22). Some of these Pdx1− endodermal cells give rise to hepatoblasts. wnt2bb is expressed in the LPM from 18 hpf (dark blue) (102); the early hepatoblast marker Prox1 starts to be expressed in endodermal cells (red) anterior to the Pdx1+ domain from 24 hpf and is continuously expressed in the liver (L) (35). fgf10a is expressed in the LPM surrounding the Pdx1+ domain from 30 hpf (orange), and appears to repress hepatic competence (123). Ventral views of the endoderm and endoderm‐derived organs, anterior up.



Figure 3.

Representation of hepatic morphogenesis. Hepatoblasts, which are the hepatic progenitors, undergo expansion via balanced cell proliferation and survival. These bipotential stem cells then differentiate into hepatocytes or cholangiocytes (biliary epithelial cells). As the morphogenesis continues, these cells undergo maturation by acquiring additional characteristics such as polarity and now are primed to perform key cellular functions of the liver.



Figure 4.

Cellular and molecular basis of hepatoblast expansion. Various mesenchymal elements including endothelial cells, hepatic stellate cells and even hematopoietic stem cells (HSCs) are a source of key growth factors that act via paracrine mechanisms to induce proliferation of hepatoblasts that expresses receptors as well as key downstream effectors of these signaling mechanisms. Abbreviations: HGF‐hepatocyte growth factor; FGF(R)‐fibroblast growth factor (receptor); BMP(R)‐bone morphogenic protein (receptor); RAR‐retinoic acid receptor; JNK‐JUN NH2‐terminal kinase; PI3K‐phosphoinositide 3‐kinase; MAPK‐mitogen activated protein kinase.



Figure 5.

Molecular basis of cholangiocyte differentiation and maturation. Various instructive signals, either paracrine or autocrine, stimulate specification of cholangiocytes from the hepatoblasts and these signals induce specific transcription factor programs within the cholangiocytes. Once these cells are specified, they continue to respond to various growth factors, again in an autocrine or paracrine fashion, to mature and organize as ductal structures with specific functions. Abbreviations: TGFβ‐transforming growth factor β; HGF‐hepatocyte growth factor; FGF‐fibroblast growth factor; BMP‐bone morphogenic protein.



Figure 6.

Molecular basis of hepatocyte differentiation and maturation. Various instructive signals, either paracrine or autocrine, stimulate specification of hepatocytes from the hepatoblasts and these signals induce specific transcription factor programs within the hepatocytes. Once these cells are specified, they continue to respond to various growth factors, again in an autocrine or paracrine fashion, to mature, acquire cell polarity and gain expression of genes to enable specific functions.



Figure 7.

Diagrams depicting hepatocyte differentiation from embryonic stem (ES) or induced pluripotent stem (iPS) cells and the direct reprogramming of fibroblasts. Exogenous factors that induce differentiation are written in red; transcription factors that are required for fibroblast reprogramming are written in blue.

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Article Title: Cellular and Molecular Basis of Liver Development
 

How to Cite

Donghun Shin, Satdarshan Pal Singh Monga. Cellular and Molecular Basis of Liver Development. Compr Physiol 2013, 3: 799-815. doi: 10.1002/cphy.c120022