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Publications (56)
The liver field has been debating for decades the contribution of the plasticity of the two epithelial compartments in the liver, hepatocytes and biliary epithelial cells (BECs), to derive each other as a repair mechanism. The hepatobiliary plasticity has been first observed in diseased human livers by the presence of biphenotypic cells expressing...
The remarkable ability of the liver to regenerate by proliferation of mature hepatocytes constitutes the first mechanism of repair commonly named the hepatocyte-driven regeneration. Yet, during chronic liver injury or acute severe hepatocyte death, proliferation of mature cells becomes exhausted. In these cases, alternative precursors of hepatocyte...
In this issue of Cell Stem Cell, Gómez-Salinero et al. (2022) identify c-Maf as a driver for murine liver sinusoidal endothelial cell (LSEC) fate and function during liver development, homeostasis, and repair. Similarly, c-Maf defines human LSECs, and its overexpression specializes generic HUVECs into functional induced-LSECs, potentiating regenera...
With the recent availability of the SARS-CoV-2 mRNA-based vaccines, public attention has been drawn to this new technology and how it may be applied to other indications. Temporal activation of key hepatic regenerative pathways can induce liver regeneration, overcoming the lack of donor organs for liver transplantation and ineffectiveness of altern...
Induction of intrinsic liver regeneration is an unmet need that can be achieved by temporally activating key hepatocyte regenerative pathways. Here, we establish an efficient, safe, non-integrative method to transiently express hepatocyte-growth-factor (HGF) and epidermal-growth-factor (EGF) in hepatocytes via nucleoside-modified, lipid-nanoparticl...
Liver organogenesis requires complex cell-cell interactions between hepatic endoderm cells and adjacent cell niches. Endothelial cells are key players for endoderm hepatic fate decision. We previously demonstrated that the endothelial cell niche promotes hepatic specification of mouse embryonic stem cell(ESC)-derived endoderm through dual repressio...
The recent identification of progenitor populations that contribute to the developing heart in a distinct spatial and temporal manner has fundamentally improved our understanding of cardiac development. However, the mechanisms that direct atrial versus ventricular specification remain largely unknown. Here we report the identification of a progenit...
Confocal z-stack animation of whole mount immunofluorescence of E8.25 Foxa2Cre:YFP embryo using antibodies against YFP (green), Nkx2-5 (red), and Isl1 (blue). Slices are shown in a posterior to anterior direction. Data reflects z-projections shown in Figure 4d and Supplementary Figure 9c.
High magnification confocal z-stack animation of whole mount immunofluorescence of E8.25 Foxa2Cre:YFP embryo using antibodies against YFP (green), Nkx2-5 (red), and Isl1 (blue). Slices are shown in a posterior to anterior direction. Data reflects z-projections shown in Supplementary Figure 9a, b.
3D volume of confocal z-projection of E9.5 Foxa2Cre:Isl1lox/lox embryo analysed by whole mount immunofluorescence (WMIF) using antibodies against cTnT (green), and Nkx2-5 (red). Data reflects z-projections shown in Figure 8d.
3D volume of confocal z-projection of E8.25 Foxa2Cre:YFP embryo analysed by whole mount immunofluorescence (WMIF) using antibodies against YFP (green), Nkx2-5 (red), and Hcn4 (blue). Data reflects z-projections shown in Figure 4b.
3D surface rendering generated from confocal z-projeciton of whole mount immunofluorescence of E8.5 Foxa2Cre:YFP embryo using antibodies against YFP (green), cTnT (red), and Isl1 (blue). 3D surfaces were generated for cTnT and Isl1. Two YFP surfaces were generated: one from the total signal, and a second using the cTnT surface to mask the YFP signa...
3D surface rendering generated from confocal z-projection of E9.5 Foxa2Cre:Isl1lox/lox embryo analysed by whole mount immunofluorescence (WMIF) using antibodies against cTnT (green). Data reflects z-projections shown in Figure 8d.
Supplementary Figures.
3D surface rendering generated from confocal z-projeciton of whole mount immunofluorescence of E8.25 Foxa2Cre:YFP embryo using antibodies against YFP (green), Nkx2-5 (red), and Hcn4 (blue). 3D surfaces were generated for Nkx2-5 and Hcn4 and the Hcn4 surface was then used to mask the YFP signal before generating the YFP surface. The YFP surface thus...
3D surface rendering generated from confocal z-projeciton of whole mount immunofluorescence of E8.25 Foxa2Cre:YFP embryo using antibodies against YFP (green), Nkx2-5 (red), and Isl1 (blue). 3D surfaces were generated for Nkx2-5 and Isl1 and the Isl1 surface was then used to mask the YFP signal before generating the YFP surface. The YFP surface thus...
3D volume of confocal z-projection of E8.5 Foxa2Cre:YFP embryo analysed by whole mount immunofluorescence (WMIF) using antibodies against YFP (green), cTnT (red), and Isl1 (blue). Data reflects z-projections shown in Figure 4i.
3D volume of confocal z-projection of E9.5 WT embryo analysed by whole mount immunofluorescence (WMIF) using antibodies against cTnT (green), and Nkx2-5 (red). Data reflects z-projections shown in Figure 8d.
3D surface rendering generated from confocal z-projection of E9.5 WT embryo analysed by whole mount immunofluorescence (WMIF) using antibodies against cTnT (green). Data reflects z-projections shown in Figure 8d.
Confocal z-stack animation of whole mount immunofluorescence of E8.25 Foxa2Cre:YFP embryo using antibodies against YFP (green), Nkx2-5 (red), and Hcn4 (blue). Slices are shown in a posterior to anterior direction. Data reflects z-projections shown in Figure 4b.
3D volume of confocal z-projection of E8.25 Foxa2Cre:YFP embryo analysed by whole mount immunofluorescence (WMIF) using antibodies against YFP (green), Nkx2-5 (red), and Isl1 (blue). Data reflects z-projections shown in Figure 4d.
In the early fetal liver, hematopoietic progenitors expand and mature together with hepatoblasts, the liver progenitors of hepatocytes and cholangiocytes. Previous analyses of human fetal livers indicated that both progenitors support each other's lineage maturation and curiously share some cell surface markers including CD34 and CD133. Using the h...
The severe shortage of organ donors for treating patients with liver disease has prompted in vitro efforts to produce the main functional cells of the liver: hepatocyte-like cells (Hep cells). We consider the key challenges posed by various stem cell technologies and liver pathologies for developing clinically useful Hep cells.
Epithelial-mesenchymal transition (EMT) and the mesenchymal-epithelial transition (MET) are processes required for embryo organogenesis. Liver develops from the epithelial foregut endoderm from which the liver progenitors, hepatoblasts, are specified. The migrating hepatoblasts acquire a mesenchymal phenotype to form the liver bud. In mid-gestation...
The liver is a central regulator of metabolism, and liver failure thus constitutes a major health burden. Understanding how this complex organ develops during embryogenesis will yield insights into how liver regeneration can be promoted and how functional liver replacement tissue can be engineered. Recent studies of animal models have identified ke...
Organogenesis requires expansion of the embryonic vascular plexus that migrates into developing organs through a process called angiogenesis. Mesodermal progenitors are thought to derive endothelial cells (ECs) that contribute to both embryonic vasculogenesis and the subsequent organ angiogenesis. Here, we demonstrate that during development of the...
The kidney's complex spatial organization and poorly defined lineage specification programs have impeded derivation of kidney progenitors from pluripotent stem cells (PSCs). Now in Cell Stem Cell, Taguchi et al. (2014) redefine the identity of embryonic kidney progenitors in vivo to obtain PSC-derived kidney progenitors that can form nephrons in vi...
The narrow species tropism of hepatitis C virus (HCV) limits animal studies. We found that pigtail macaque (Macaca nemestrina) hepatic cells derived from induced pluripotent stem cells support the entire HCV life cycle, although infection efficiency was limited by defects in the HCV cell entry process. This block was overcome by either increasing o...
Understanding the fetal hepatic niche is essential for optimizing the generation of functional hepatocyte-like cells (hepatic cells) from human embryonic stem cells (hESCs). Here, we show that KDR (VEGFR2/FLK-1), previously assumed to be mostly restricted to mesodermal lineages, marks a hESC-derived hepatic progenitor. hESC-derived endoderm cells d...
Liver diseases affect millions of people worldwide, especially in developing countries. According to the American Liver Foundation, nearly 1 in every 10 Americans suffers from some form of liver disease. Even though, the liver has great ability to self-repair, in end-stage liver diseases including fibrosis, cirrhosis, and liver cancer induced by vi...
Cell based treatments for myocardial infarction have demonstrated efficacy in the laboratory and in phase I clinical trials, but the understanding of such therapies remains incomplete. Mesenchymal stem cells (MSCs) are classically defined as maintaining the ability to generate mesenchyme-derived cell types, namely adipocytes, chondrocytes and osteo...
Oligonucleotide primers used for PCR.
(RTF)
Microarray gene expression analysis. Tet-pdx1/ngn3 ES cells were cultured according to Protocol #2 with BMP4 and cultured in suspension. Pdx1 and Ngn3 were induced with or without Dox starting at day 4, and cells were harvested at the indicated time points. RNA samples were isolated from day 13 EBs with or without Dox, βTC6 cells and e15.5 mouse em...
Time course of pancreatic gene expression. Tet-pdx1/ngn3 ES cells were cultured according to Protocol #2 with BMP4 and cultured in suspension. Pdx1 and Ngn3 were induced with or without Dox starting at day 4, and cells were harvested at the indicated time points. Various pancreatic related-genes were analyzed by microarrays. Dox(−); open squares, D...
Protocol for culture conditions.
(RTF)
In order to define the molecular mechanisms regulating the specification and differentiation of pancreatic β-islet cells, we investigated the effect of upregulating Pdx1 and Ngn3 during the differentiation of the β-islet-like cells from murine embryonic stem (ES) cell-derived activin induced-endoderm. Induced overexpression of Pdx1 resulted in a si...
The directed differentiation of iPS and ES cells into definitive endoderm (DE) would allow the derivation of otherwise inaccessible progenitors for endodermal tissues. However, a global comparison of the relative equivalency of DE derived from iPS and ES populations has not been performed. Recent reports of molecular differences between iPS and ES...
Directed differentiation of human embryonic stem (hES) cells and human induced pluripotent stem (hiPS) cells captures in vivo developmental pathways for specifying lineages in vitro, thus avoiding perturbation of the genome with exogenous genetic material. Thus far, derivation of endodermal lineages has focused predominantly on hepatocytes, pancrea...
Complex cross-talk between endoderm and the microenvironment is an absolute requirement to orchestrate hepatic specification and expansion. In the mouse, the septum transversum and cardiac mesoderm, through secreted bone morphogenetic proteins (BMP) and fibroblast growth factors (FGF), respectively, instruct the adjacent ventral endoderm to become...
Krüppel-like factor 6 (Klf6; copeb in zebrafish) is a zinc-finger transcription factor and tumor suppressor gene. Klf6(-)(/)(-) mice have defects in hematopoiesis and angiogenesis and do not form a liver. However, the vascular abnormalities in Klf6(-/-) mice obfuscate its role in liver development since these two processes are linked in mammals. We...
The development of functional cell populations such as hepatocytes and pancreatic β cells from embryonic stem cell (ESC) is dependent on the efficient induction of definitive endoderm early in the differentiation process. To monitor definitive endoderm formation in mouse ESC differentiation cultures in a quantitative fashion, we generated a reporte...
When differentiated in the presence of activin A in serum-free conditions, mouse embryonic stem cells efficiently generate an endoderm progenitor population defined by the coexpression of either Brachyury, Foxa2 and c-Kit, or c-Kit and Cxcr4. Specification of these progenitors with bone morphogenetic protein-4 in combination with basic fibroblast g...
Development of the ductal network in the mammary gland is dependent in part on the presence of macrophages. Here we utilize multi-photon microscopy and second harmonic generation to describe terminal end bud 3-dimensional structure and the organization of the surrounding collagen matrix. We have applied this approach to analyze the effect of macrop...
Macrophages play an important role in organ development, tissue homeostasis, and remodeling. Thus, we monitored the presence of F4/80-positive macrophages in the pancreas of wild-type mice, and some developmental features of this complex tissue were compared throughout life in wild-type and macrophage-deficient Csf1op/Csf1op (op/op) mice. The combi...
Mammary epithelial cells are embedded in a unique extracellular environment to which adipocytes and other stromal cells contribute. Mammary epithelial cells are critically dependent on this milieu for survival. However, it remains unknown which adipocyte-secreted factors are required for the survival of the mammary epithelia and what role these adi...
Mammary fat tissue is crucial for mammary ductal morphogenesis in both fetal and adult mice. There are two kinds of adipocytes, the energy-storing white and the energy-dissipating brown adipocyte. The precise identity of the types of adipocyte in the mammary gland has never been investigated but was always assumed to be only white fat. In this stud...
Colony stimulating factor 1 (CSF-1), a major regulator of the mononuclear phagocytic lineage, is expressed in more than 70% of human breast cancers and its expression is correlated with poor prognosis. Studies of CSF-1 null mutant mice demonstrated that CSF-1 plays an important role in normal mammary ductal development as well as in mammary tumor p...
Epithelial/mesenchymal cell interactions are necessary for proper ductal morphogenesis throughout all stages of mammary gland development. Besides the well-established stromal components, such as adipocytes and fibroblasts, the mammary stroma is also infiltrated with migrating blood cells, mostly macrophages and eosinophils. The focus of this revie...
The presence of eosinophils in the endometrium of rodents during the estrous cycle or after E2 administration to ovariectomized animals is well documented. Nevertheless, the chemoattractant for eosinophils and the function of E-dependent eosinophils during the estrous cycle remain unknown. Using mice homozygous for a null mutation in the gene for e...
Interactions between mammary epithelial and mesenchymal cells including fibroblasts and adipocytes are crucial for the proper postnatal development of the mammary ductal tree. Often overlooked, however, are the migrant cells that enter tissues at different stages of development. In this paper we identify two such cell types, macrophages and eosinop...
