KDR Identifies a Conserved Human and Murine Hepatic Progenitor and Instructs Early Liver Development

Abstract

SUMMARY Understanding the fetal hepatic niche is essential for optimizing the generation of functional hepatocyte-like (hepatic) cells from human embryonic stem cells (hESCs). Here, we show that KDR (VEGFR2), previously assumed to be mostly restricted to mesodermal lineages, marks a hESC-derived hepatic progenitor. hESC-derived endoderm cells do not express KDR, but when cultured in media supporting hepatic differentiation, generate KDR+ hepatic progenitors and KDR- hepatic cells. KDR+ progenitors require active KDR signaling both to instruct their own differentiation into hepatic cells, and to support non-cell-autonomously the functional maturation of co-cultured KDR- hepatic cells. Analysis of human fetal livers suggests that similar progenitors are present in human livers. Lineage tracing in mice provides in vivo evidence of a KDR+ hepatic progenitor for fetal hepatoblasts and subsequently adult hepatocytes and cholangiocytes. Altogether, our findings reveal that KDR is a conserved marker for endoderm-derived hepatic progenitors, and a functional receptor instructing early liver development.

Endoderm Generates Endothelial Cells during Liver Development

“…All these KDR+ progenitors are of mesodermal origin. Our previous study provided the first evidence for the existence of a KDR+ progenitor for liver, an endoderm derivative (Goldman et al., 2013). Given the well-documented studies on the bipotentiality of a KDR+ progenitor for the EC lineage and mesodermal derivatives, it should perhaps not be surprising that we were able to document the bipotentiality of an endoderm-derived KDR+ progenitor for hepatic endoderm cells and ECs using clonal assays.…”

“…Our previous work revealed the existence of KDR-expressing hepatic progenitors (KDR+ progenitor) in human embryonic stem cell (hESC) cultures differentiated toward the hepatic lineage (Goldman et al., 2013). Isolated hESC-derived endoderm cells give rise to both the KDR+ hepatic progenitors and the committed KDR− hepatic cells.…”

Functional Characteristics of Reversibly Immortalized Hepatic Progenitor Cells Derived from Mouse Embryonic Liver

“…It has been widely reported that hepatocytes can be derived from embryonic stem cells, mesenchymal stem cells, and iPS cells [13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28]. While these progenitor/stem cells are potentially important sources for hepatocyte transplantation, the lineage-specificity and differentiation efficiency of these progenitor cells remain to be fully characterized in vivo .…”

“…This matter is further complicated by our current lack of the knowledge and understanding of the detailed mechanism through which hepatic progenitors are regulated and directed to hepatocyte lineage-specific differentiation. Thus, liver progenitor cells isolated from both fetal and adult liver tissues should have the inherited advantages over those extrahepatic sources of stem cells [1,21,29,30,31,32,33,34,35,36]. …”

“…The onset of mouse liver development starts at embryonic day (E) 8.5 from the foregut endoderm, which is derived from medial and lateral domains of developing ventral foregut [12]. While numerous studies reported that hepatocytes can be derived from embryonic stem cells, mesenchymal stem cells, and iPS cells [13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28], liver progenitor cells have been isolated from both fetal and adult liver tissues, which have the capacity for unlimited proliferation and multilineage differentiation [1,21,29,30,31,32,33,34,35,36]. Although it has been reported that relatively long-term culturing of liver progenitor cells can be achieved under special culture conditions [31,37,38,39], the primary progenitor cells usually have limited life span in vitro [40,41].…”