Foxl1-Cre-marked adult hepatic progenitors have clonogenic and bilineage differentiation potential.

Isolation of hepatic progenitor cells is a promising approach for cell replacement therapy of chronic liver disease. The winged helix transcription factor Foxl1 is a marker for progenitor cells and their descendants in the mouse liver in vivo. Here, we purify progenitor cells from Foxl1-Cre; RosaYFP mice and evaluate their proliferative and differentiation potential in vitro. Treatment of Foxl1-Cre; RosaYFP mice with a 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet led to an increase of the percentage of YFP-labeled Foxl1(+) cells. Clonogenic assays demonstrated that up to 3.6% of Foxl1(+) cells had proliferative potential. Foxl1(+) cells differentiated into cholangiocytes and hepatocytes in vitro, depending on the culture condition employed. Microarray analyses indicated that Foxl1(+) cells express stem cell markers such as Prom1 as well as differentiation markers such as Ck19 and Hnf4a. Thus, the Foxl1-Cre; RosaYFP model allows for easy isolation of adult hepatic progenitor cells that can be expanded and differentiated in culture.

Expression and function of scalloped during Drosophila development.

BACKGROUND: The scalloped (sd) and vestigial (vg) genes function together in Drosophila wing development. Little is known about sd protein (SD) expression during development, or whether sd and vg interact in other developing tissues. To begin to address these questions, we generated an anti-SD antibody. RESULTS: During embryogenesis, SD is expressed in both central and peripheral nervous systems, and the musculature. SD is also expressed in developing flight appendages. Despite SD expression herein, the peripheral nervous system, musculature, and dorsal limb primordia appeared generally normal in the absence of sd function. SD is also expressed in subsets of ventral nerve cord cells, including neuroblast 1-2 descendants and ventral unpaired median motor neurons (mVUMs). While sd function is not required to specify these neurons, it is necessary for the correct innervation of somatic muscles by the mVUMs. We also show that SD and vg protein (VG) are co-expressed in overlapping and distinctive subsets of cells in embryonic and larval tissues. CONCLUSIONS: We describe the full breadth of SD expression during Drosophila embryogenesis, and identify a requirement for sd function in a subset of motor neurons. This work provides the necessary foundation for functional studies regarding the roles of sd during Drosophila development.

Foxl1 is a marker of bipotential hepatic progenitor cells in mice.

UNLABELLED: The liver contains a population of small bipotential facultative progenitor cells that reconstitute liver function when mature hepatocytes or cholangiocytes are unable to proliferate. Mesenchymal markers, including members of the forkhead transcription factor gene family, have been detected in hepatic progenitor cells. The winged helix transcription factor Foxl1 localizes to mesenchymal cells in the intestine; however, its expression in the liver has not been reported. We found that Foxl1 is expressed in rare cells in the normal liver but is dramatically induced in the livers of mice that have undergone bile duct ligation or were fed a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-containing or choline-deficient, ethionine-supplemented diet. In addition, we employed genetic lineage tracing using a Foxl1-Cre transgenic mouse crossed with the Rosa26R lacZ reporter line to demonstrate that Foxl1-Cre-expressing cells are present within the periportal region shortly after injury. These cells give rise to both hepatocytes [marked by hepatocyte nuclear factor 4 alpha (HNF-4alpha) expression] and cholangiocytes (marked by CK19 expression), indicating that these cells are derived from Foxl1-Cre-expressing cells. Foxl1-Cre-expressing cells are distinct from hepatic stellate cells, portal fibroblasts, and myofibroblasts, although they are located in close proximity to portal fibroblasts. These results demonstrate that the early Foxl1-Cre lineage cell gives rise to both cholangiocytes and hepatocytes after liver injury and suggest the potential for progenitor-portal fibroblast cell interactions. CONCLUSION: We propose that Foxl1 is a bona fide marker of the facultative progenitor cell in the mouse liver.

Foxl1 promotes liver repair following cholestatic injury in mice.

Cholangiocyte proliferation is one of the hallmarks of the response to cholestatic injury. We previously reported that the winged helix transcription factor Foxl1 is dramatically induced in cholangiocytes following bile duct ligation. In this study, we investigated the function of Foxl1 in the bile duct ligation model of cholestatic liver injury in Foxl1(-/-) and control mice. We found that Foxl1(-/-) livers exhibit an increase in parenchymal necrosis, significantly impaired cholangiocyte and hepatocyte proliferation, and failure to expand bile ductular mass. Wnt3a and Wnt7b expression was decreased in the livers of Foxl1(-/-) mice along with reduced expression of the beta-catenin target gene Cyclin D1 in Foxl1(-/-) cholangiocytes. These results show that Foxl1 promotes liver repair after bile-duct-ligation-induced liver injury through activation of the canonical wnt/beta-catenin pathway.