Evidence for a common progenitor of epithelial and mesenchymal components of the liver

Abstract

Tissues of the adult organism maintain the homeostasis and respond to injury by means of progenitor/stem cell compartments capable to give rise to appropriate progeny. In organs composed by histotypes of different embryological origins (e.g. the liver), the tissue turnover may in theory involve different stem/precursor cells able to respond coordinately to physiological or pathological stimuli. In the liver, a progenitor cell compartment, giving rise to hepatocytes and cholangiocytes, can be activated by chronic injury inhibiting hepatocyte proliferation. The precursor compartment guaranteeing turnover of hepatic stellate cells (HSCs) (perisinusoidal cells implicated with the origin of the liver fibrosis) in adult organ is yet unveiled. We show here that epithelial and mesenchymal liver cells (hepatocytes and HSCs) may arise from a common progenitor. Sca þ murine progenitor cells were found to coexpress markers of epithelial and mesenchymal lineages and to give rise, within few generations, to cells that segregate the lineage-specific markers into two distinct subpopulations. Notably, these progenitor cells, clonally derived, when transplanted in healthy livers, were found to generate epithelial and mesenchymal liver-specific derivatives (i.e. hepatocytes and HSCs) properly integrated in the liver architecture. These evidences suggest the existence of a 'bona fide' organ-specific meso-endodermal precursor cell, thus profoundly modifying current models of adult progenitor commitment believed, so far, to be lineage-restricted. Heterotopic transplantations, which confirm the dual differentiation potentiality of those cells, indicates as tissue local cues are necessary to drive a full hepatic differentiation. These data provide first evidences for an adult stem/ precursor cell capable to differentiate in both parenchymal and non-parenchymal organ-specific components and candidate the liver as the instructive site for the reservoir compartment of HSC precursors as yet non-localized in the adult. In many postnatal organs, physiological cell turnover and restoration of cell loss after injury are maintained by progenitor/ stem cell compartments residing in specialized niches. 1-3Concerning the liver, its ability to regenerate is largely based on the proliferation of terminally differentiated parenchymal liver cells (hepatocytes and cholangiocytes); however, when the proliferation of mature epithelial cells is inhibited by exposure to drugs or by chronic injury, a progenitor cell compartment emerges. 4,5 These progenitor cells, known as 'oval cells' in rodents, and proven to constitute a heterogeneous cell population, 6 are characterized by the expression of markers of both cholangiocytes and hepatocytes and by a high proliferative potential in all species. The progenitors are regarded as bipotential transient amplifying cells, 7,8 downstream of a normally quiescent true stem cell. With respect to the mesenchymal hepatic stellate cells (HSC), while their embryonic derivation from septum transversum mesenchyme and from me...

Molecular mechanisms controlling the phenotype and the EMT/MET dynamics of hepatocyte

“…From these transitional cells, a population of genetically marked hepatocytes, able to repopulate large areas of the hepatic parenchyma, emerged. Consistent with these results is the recent evidence, collected by Conigliaro et al (54), that metastable hepatic stem/progenitor cells, isolated from embryonic livers and established in clonally derived cell lines, give rise to both hepatocytes and HSCs when injected into normal growing liver.…”

“…Consistent with these results is the recent evidence, collected by Conigliaro et al . , that metastable hepatic stem/progenitor cells, isolated from embryonic livers and established in clonally derived cell lines, give rise to both hepatocytes and HSCs when injected into normal growing liver.…”

Operating principles of Notch–Delta–Jagged module of cell–cell communication

“…Activation of EMT in cancer cells also leads to an increase in their tumor-initiating capabilities or transform them to being like CSCs-the therapy-resistant cancer cells that act as a reservoir for new, more differentiated tumor cells, as well as maintain the ability to self-renew for many generations, thereby initiating a tumor [82,83]. Recent studies show that cells undergoing partial EMT can gain 'stemness' that can be compromised significantly if cells undergo complete EMT and become mesenchymal-like [47,[84][85][86][87]; thereby highlighting another advantage of collectively migrating CTCs during metastatic progression. All these functional advantages of collective cell migration or hybrid E/M phenotype-resistance to cell death during circulation, higher plasticity to both colonize and reinitiate metastasis, and enhanced tumor-initiating abilities-might be attained only in the presence of the cell-cell communication based stabilizing interactions provided by NDJ signaling ( figure 9(B)).…”

Myofibroblastic cells function as progenitors to regenerate murine livers after partial hepatectomy

“…Adult HSC coexpress mesodermal markers (eg, Lhx, Wilms tumour-1), ectodermal markers (eg, Nestin, GFAP)37–40 and endoderm-enriched genes (eg, FoxA2, HNF4α, albumin),5 41 plus transcription factors associated with stem/progenitor cells (eg, Nanog, Oct4) 37 42–45. Depending on culture conditions, HSC from adult livers can generate bone-like, fat-like, neural-like, cholangiocyte-like or hepatocyte-like cells,40 43 46 demonstrating inherent plasticity. Pancreatic stellate cells (which closely resemble HSC) repopulated the hepatocyte compartment when transplanted after PH,47 suggesting that some HSC can be reprogrammed in vivo.…”