scholarly journals Fate and functional roles of Prominin 1+ cells in liver injury and cancer

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Raymond Wu ◽  
Stephanie Pan ◽  
Yibu Chen ◽  
Yasuhiro Nakano ◽  
Meng Li ◽  
...  
Keyword(s):  
Rna Sequencing ◽  
Bioinformatic Analysis ◽  
Lineage Tracing ◽  
Genetic Lineage ◽  
Sequencing Analysis ◽  
Ductular Reaction ◽  
Functional Roles ◽  
Genetic Lineage Tracing ◽  
Relevant Gene ◽  
Human Alcoholic

Abstract Prominin 1 (PROM1) is one of a few clinically relevant progenitor markers in human alcoholic hepatitis (AH) and hepatocellular carcinoma (HCC), and mouse liver tumor initiating stem cell-like cells (TICs). However, the origin, fate and functions of PROM1+ cells in AH and HCC are unknown. Here we show by genetic lineage tracing that PROM1+ cells are derived in part from hepatocytes in AH and become tumor cells in mice with diethyl nitrosamine (DEN)-initiated, Western alcohol diet-promoted liver tumorigenesis. Our RNA sequencing analysis of mouse PROM1+ cells, reveals transcriptomic landscapes indicative of their identities as ductular reaction progenitors (DRPs) and TICs. Indeed, single-cell RNA sequencing reveals two subpopulations of Prom1+ Afp– DRPs and Prom1+ Afp+ TICs in the DEN-WAD model. Integrated bioinformatic analysis identifies Discodin Domain Receptor 1 (DDR1) as a uniquely upregulated and patient-relevant gene in PROM1+ cells in AH and HCC. Translational relevance of DDR1 is supported by its marked elevation in HCC which is inversely associated with patient survival. Further, knockdown of Ddr1 suppresses the growth of TICs and TIC-derived tumor growth in mice. These results suggest the importance of PROM1+ cells in the evolution of liver cancer and DDR1 as a potential driver of this process.

scholarly journals SETD4-expressing cells contribute to pancreatic development and response to cerulein induced pancreatitis injury

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jin-Ze Tian ◽  
Sheng Xing ◽  
Jing-Yi Feng ◽  
Shu-Hua Yang ◽  
Yan-Fu Ding ◽  
...  
Keyword(s):  
Cell Population ◽  
Acinar Cells ◽  
Pancreatic Disease ◽  
Lineage Tracing ◽  
Genetic Lineage ◽  
Pancreatic Development ◽  
Histone Lysine Methyltransferase ◽  
Population Potential ◽  
Potential Applications ◽  
Genetic Lineage Tracing

AbstractIn the adult pancreas, the presence of progenitor or stem cells and their potential involvement in homeostasis and regeneration remains unclear. Here, we identify that SET domain-containing protein 4 (SETD4), a histone lysine methyltransferase, is expressed in a small cell population in the adult mouse pancreas. Genetic lineage tracing shows that during pancreatic development, descendants of SETD4+ cells make up over 70% of pancreatic cells and then contribute to each pancreatic lineage during pancreatic homeostasis. SETD4+ cells generate newborn acinar cells in response to cerulein-induced pancreatitis in acinar compartments. Ablation of SETD4+ cells compromises regeneration of acinar cells, in contrast to controls. Our findings provide a new cellular narrative for pancreatic development, homeostasis and response to injury via a small SETD4+ cell population. Potential applications may act to preserve pancreatic function in case of pancreatic disease and/or damage.

scholarly journals Hlf Expression Marks Early Emergence of Hematopoietic Stem Cell Precursors With Adult Repopulating Potential and Fate

2021 ◽  
Vol 9 ◽  
Author(s):  
Wanbo Tang ◽  
Jian He ◽  
Tao Huang ◽  
Zhijie Bai ◽  
Chaojie Wang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mouse Model ◽  
Hematopoietic Stem Cells ◽  
Fetal Liver ◽  
Lineage Tracing ◽  
Genetic Lineage ◽  
Hematopoietic Stem ◽  
Genetic Lineage Tracing

In the aorta-gonad-mesonephros (AGM) region of mouse embryos, pre-hematopoietic stem cells (pre-HSCs) are generated from rare and specialized hemogenic endothelial cells (HECs) via endothelial-to-hematopoietic transition, followed by maturation into bona fide hematopoietic stem cells (HSCs). As HECs also generate a lot of hematopoietic progenitors not fated to HSCs, powerful tools that are pre-HSC/HSC-specific become urgently critical. Here, using the gene knockin strategy, we firstly developed an Hlf-tdTomato reporter mouse model and detected Hlf-tdTomato expression exclusively in the hematopoietic cells including part of the immunophenotypic CD45– and CD45+ pre-HSCs in the embryonic day (E) 10.5 AGM region. By in vitro co-culture together with long-term transplantation assay stringent for HSC precursor identification, we further revealed that unlike the CD45– counterpart in which both Hlf-tdTomato-positive and negative sub-populations harbored HSC competence, the CD45+ E10.5 pre-HSCs existed exclusively in Hlf-tdTomato-positive cells. The result indicates that the cells should gain the expression of Hlf prior to or together with CD45 to give rise to functional HSCs. Furthermore, we constructed a novel Hlf-CreER mouse model and performed time-restricted genetic lineage tracing by a single dose induction at E9.5. We observed the labeling in E11.5 AGM precursors and their contribution to the immunophenotypic HSCs in fetal liver (FL). Importantly, these Hlf-labeled early cells contributed to and retained the size of the HSC pool in the bone marrow (BM), which continuously differentiated to maintain a balanced and long-term multi-lineage hematopoiesis in the adult. Therefore, we provided another valuable mouse model to specifically trace the fate of emerging HSCs during development.

scholarly journals Unraveling the transcriptional networks that drive oligodendrocyte fate specification in Sonic hedgehog-responsive neocortical progenitors

2020 ◽  
Author(s):  
Caitlin C. Winkler ◽  
Luuli N. Tran ◽  
Ellyn P. Milan ◽  
Fernando García-Moreno ◽  
Santos J. Franco
Keyword(s):  
Sonic Hedgehog ◽  
Wild Type Mouse ◽  
Lineage Tracing ◽  
Human Embryos ◽  
Transcriptional Networks ◽  
Genetic Lineage ◽  
Gene Regulatory ◽  
Oligodendrocyte Precursor ◽  
Genetic Lineage Tracing ◽  
Developing Nervous System

In the developing nervous system, progenitors first generate neurons before making astrocytes and oligodendrocytes. We previously showed that increased Sonic hedgehog (Shh) signaling in dorsal forebrain progenitors is important for their production of oligodendrocytes as neurogenesis winds down. Here, we analyzed single-cell RNA sequencing datasets to better understand how Shh controls this neuron-to-oligodendrocyte switch in the neocortex. We first identified Shh-responding progenitors using a dataset in which Shh was overexpressed in the mouse dorsal forebrain. Pseudotime trajectory inferences revealed a subpopulation committed to the oligodendrocyte precursor cell (OPC) lineage. Genes upregulated along this lineage defined a pre-OPC state, as cells transitioned from progenitors to OPCs. Using several datasets from wild-type mouse and human embryos at different ages, we confirmed a pre-OPC state preceding OPC emergence during normal development. Finally, we show that pre-OPCs are enriched for a gene regulatory network involving the transcription factor Ascl1. Genetic lineage-tracing demonstrated Ascl1+ dorsal progenitors primarily make oligodendrocytes. We propose a model in which Shh shifts the balance between opposing transcriptional networks toward an Ascl1 lineage, thereby facilitating the switch between neurogenesis and oligodendrogenesis.

scholarly journals Reactivation of the Epicardium at the Origin of Myocardial Fibro-Fatty Infiltration During the Atrial Cardiomyopathy

2020 ◽  
Vol 126 (10) ◽  
pp. 1330-1342 ◽  
Author(s):  
Nadine Suffee ◽  
Thomas Moore-Morris ◽  
Bernd Jagla ◽  
Nathalie Mougenot ◽  
Gilles Dilanian ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Cell Fate ◽  
Wilms Tumor ◽  
Fatty Infiltration ◽  
Growth Factor Receptor ◽  
Lineage Tracing ◽  
Right Atrial ◽  
Genetic Lineage ◽  
Specific Cell ◽  
Sequencing Analysis

Rationale: Fibro-fatty infiltration of subepicardial layers of the atrial wall has been shown to contribute to the substrate of atrial fibrillation. Objective: Here, we examined if the epicardium that contains multipotent cells is involved in this remodeling process. Methods and Results: One hundred nine human surgical right atrial specimens were evaluated. There was a relatively greater extent of epicardial thickening and dense fibro-fatty infiltrates in atrial tissue sections from patients aged over 70 years who had mitral valve disease or atrial fibrillation when compared with patients aged less than 70 years with ischemic cardiomyopathy as indicated using logistic regression adjusted for age and gender. Cells coexpressing markers of epicardial progenitors and fibroblasts were detected in fibro-fatty infiltrates. Such epicardial remodeling was reproduced in an experimental model of atrial cardiomyopathy in rat and in Wilms tumor 1 (WT1) CreERT2/+ ;ROSA-tdT +/− mice. In the latter, genetic lineage tracing demonstrated the epicardial origin of fibroblasts within fibro-fatty infiltrates. A subpopulation of human adult epicardial-derived cells expressing PDGFR (platelet-derived growth factor receptor)-α were isolated and differentiated into myofibroblasts in the presence of Ang II (angiotensin II). Furthermore, single-cell RNA-sequencing analysis identified several clusters of adult epicardial-derived cells and revealed their specification from adipogenic to fibrogenic cells in the rat model of atrial cardiomyopathy. Conclusions: Epicardium is reactivated during the formation of the atrial cardiomyopathy. Subsets of adult epicardial-derived cells, preprogrammed towards a specific cell fate, contribute to fibro-fatty infiltration of subepicardium of diseased atria. Our study reveals the biological basis for chronic atrial myocardial remodeling that paves the way of atrial fibrillation.

scholarly journals Genetic Lineage Tracing of Sca-1 + Cells Reveals Endothelial but Not Myogenic Contribution to the Murine Heart

Circulation ◽  
2018 ◽  
Vol 138 (25) ◽  
pp. 2931-2939 ◽  
Author(s):  
Ronald J. Vagnozzi ◽  
Michelle A. Sargent ◽  
Suh-Chin J. Lin ◽  
Nathan J. Palpant ◽  
Charles E. Murry ◽  
...  
Keyword(s):  
Lineage Tracing ◽  
Genetic Lineage ◽  
Genetic Lineage Tracing

scholarly journals Troy+ brain stem cells cycle through quiescence and regulate their number by sensing niche occupancy

2018 ◽  
Vol 115 (4) ◽  
pp. E610-E619 ◽  
Author(s):  
Onur Basak ◽  
Teresa G. Krieger ◽  
Mauro J. Muraro ◽  
Kay Wiebrands ◽  
Daniel E. Stange ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Number ◽  
Lineage Tracing ◽  
Rapid Expansion ◽  
Molecular Signature ◽  
Genetic Lineage ◽  
Proliferating Cells ◽  
Self Renewal ◽  
Genetic Lineage Tracing

The adult mouse subependymal zone provides a niche for mammalian neural stem cells (NSCs). However, the molecular signature, self-renewal potential, and fate behavior of NSCs remain poorly defined. Here we propose a model in which the fate of active NSCs is coupled to the total number of neighboring NSCs in a shared niche. Using knock-in reporter alleles and single-cell RNA sequencing, we show that the Wnt target Tnfrsf19/Troy identifies both active and quiescent NSCs. Quantitative analysis of genetic lineage tracing of individual NSCs under homeostasis or in response to injury reveals rapid expansion of stem-cell number before some return to quiescence. This behavior is best explained by stochastic fate decisions, where stem-cell number within a shared niche fluctuates over time. Fate mapping proliferating cells using a Ki67iresCreER allele confirms that active NSCs reversibly return to quiescence, achieving long-term self-renewal. Our findings suggest a niche-based mechanism for the regulation of NSC fate and number.

scholarly journals Putative oncogene Brachyury (T) is essential to specify cell fate but dispensable for notochord progenitor proliferation and EMT

2016 ◽  
Vol 113 (14) ◽  
pp. 3820-3825 ◽  
Author(s):  
Jianjian Zhu ◽  
Kin Ming Kwan ◽  
Susan Mackem
Keyword(s):  
Cell Fate ◽  
Epithelial Mesenchymal Transition ◽  
Primitive Streak ◽  
Lineage Tracing ◽  
Genetic Lineage ◽  
Mesenchymal Transition ◽  
Neural Fate ◽  
Notochord Cell ◽  
Genetic Lineage Tracing ◽  
And Function

The transcription factor Brachyury (T) gene is expressed throughout primary mesoderm (primitive streak and notochord) during early embryonic development and has been strongly implicated in the genesis of chordoma, a sarcoma of notochord cell origin. Additionally, T expression has been found in and proposed to play a role in promoting epithelial–mesenchymal transition (EMT) in various other types of human tumors. However, the role of T in normal mammalian notochord development and function is still not well-understood. We have generated an inducible knockdown model to efficiently and selectively deplete T from notochord in mouse embryos. In combination with genetic lineage tracing, we show that T function is essential for maintaining notochord cell fate and function. Progenitors adopt predominantly a neural fate in the absence of T, consistent with an origin from a common chordoneural progenitor. However, T function is dispensable for progenitor cell survival, proliferation, and EMT, which has implications for the therapeutic targeting of T in chordoma and other cancers.

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