Functions and the Emerging Role of the Foetal Liver into Regenerative Medicine

Abstract

During foetal life, the liver plays the important roles of connection and transient hematopoietic function. Foetal liver cells develop in an environment called a hematopoietic stem cell niche composed of several cell types, where stem cells can proliferate and give rise to mature blood cells. Embryologically, at about the third week of gestation, the liver appears, and it grows rapidly from the fifth to 10th week under WNT/β-Catenin signaling pathway stimulation, which induces hepatic progenitor cells proliferation and differentiation into hepatocytes. Development of new strategies and identification of new cell sources should represent the main aim in liver regenerative medicine and cell therapy. Cells isolated from organs with endodermal origin, like the liver, bile ducts, and pancreas, could be preferable cell sources. Furthermore, stem cells isolated from these organs could be more susceptible to differentiate into mature liver cells after transplantation with respect to stem cells isolated from organs or tissues with a different embryological origin. The foetal liver possesses unique features given the co-existence of cells having endodermal and mesenchymal origin, and it could be highly available source candidate for regenerative medicine in both the liver and pancreas. Taking into account these advantages, the foetal liver can be the highest potential and available cell source for cell therapy regarding liver diseases and diabetes.

Keywords: foetal liver; foetal liver embryogenesis; foetal organoids; foetal stem cells; regenerative medicine.

Figure 1

Timeline of fetal hematopoiesis. Primitive hematopoietic cells appear in the yolk sac for seven weeks. Hematopoiesis is then temporarily shared between the liver, spleen, and thymus. After blood circulation starts, primitive hematopoietic cells get into the circulation and mature. At 10 weeks, hematopoietic progenitor cells gradually migrate from the aorta-mesonephros-gonad (AGM) region to colonize the liver, which becomes the major hematopoietic organ. Hematopoiesis shifts from foetal liver to bone marrow at 16 gestational weeks.

Figure 2

Maturation of hepatic, biliary, and pancreatic lineages from foregut endoderm progenitor cells. In the figure we recapitulate the embryological development, indicating key biomarkers and stimuli to induce cell differentiation. Abbreviations (in order of appearance): a, adult; e, embryonic; BTSCs, biliary tree stem/progenitor cells; PBGs, peribiliary glands; PDGs, pancreatic ductal glands; CoH, canal of Hering; BD, bile duct; AFP, alpha-fetoprotein; AMY2A, amylase 2A; CPA1, carboxypeptidase A1; SOX, sex determining region Y-box; PDX1, pancreatic and duodenal homebox 1; HNF, hepatocyte nuclear factor; Fox, forkhead box; PTF, pancreas transcription factor-like; HES1, transcription factor HES1; NGN, neurogenin; GATA, erythroid transcription factor; PAX, paired box; ARX, aristaless related homeobox; TRY, transcription factor TRY; CFTR, cystic fibrosis transmembrane conductance regulator; CPA, carboxypeptidase; FGF, fibroblast growt factor; Shh, sonic hedegehog; HGF, hepatocyte growth factor; BMP, bone morphogenetic protein; GLP-1, glucagon like peptide 1; IGF-1, insulin-like growth factor 1.