scholarly journals Cardiac Regeneration and Stem Cells

2015 ◽  
Vol 95 (4) ◽  
pp. 1189-1204 ◽  
Author(s):  
Yiqiang Zhang ◽  
John Mignone ◽  
W. Robb MacLellan
Keyword(s):  
Cardiac Myocyte ◽  
Cardiac Injury ◽  
Cardiac Regeneration ◽  
Lineage Tracing ◽  
Great Promise ◽  
Genetic Lineage ◽  
Cellular Mechanisms ◽  
Carbon 14 ◽  
Genetic Lineage Tracing ◽  
Novel Strategy

After decades of believing the heart loses the ability to regenerate soon after birth, numerous studies are now reporting that the adult heart may indeed be capable of regeneration, although the magnitude of new cardiac myocyte formation varies greatly. While this debate has energized the field of cardiac regeneration and led to a dramatic increase in our understanding of cardiac growth and repair, it has left much confusion in the field as to the prospects of regenerating the heart. Studies applying modern techniques of genetic lineage tracing and carbon-14 dating have begun to establish limits on the amount of endogenous regeneration after cardiac injury, but the underlying cellular mechanisms of this regeneration remained unclear. These same studies have also revealed an astonishing capacity for cardiac repair early in life that is largely lost with adult differentiation and maturation. Regardless, this renewed focus on cardiac regeneration as a therapeutic goal holds great promise as a novel strategy to address the leading cause of death in the developed world.

scholarly journals Abcg2-Expressing Side Population Cells Contribute to Cardiomyocyte Renewal through Fusion

2019 ◽  
Author(s):  
Amritha Yellamilli ◽  
Yi Ren ◽  
Ron T. McElmurry ◽  
Jonathan P. Lambert ◽  
Polina Gross ◽  
...  
Keyword(s):  
Side Population ◽  
Cardiac Injury ◽  
Cardiac Regeneration ◽  
Lineage Tracing ◽  
The Body ◽  
Genetic Lineage ◽  
Differentiated Cells ◽  
Cell Cycle Entry ◽  
Genetic Lineage Tracing ◽  
Regenerative Therapies

ABSTRACTThe adult mammalian heart has a limited regenerative capacity. Therefore, identification of endogenous cells and mechanisms that contribute to cardiac regeneration is essential for the development of targeted regenerative therapies. The side population (SP) phenotype enriches for stem cells throughout the body, and SP cells have been identified in the heart. We generated a novel Abcg2-driven, genetic lineage-tracing mouse model and show efficient labeling of SP cells. Labeled SP cells give rise to terminally differentiated cells in bone marrow and intestines. In the heart, we find that Abcg2-expressing SP cells contribute to cardiomyocyte labeling, which is further enhanced in response to different forms of cardiac injury. We find that cardiac SP cells fuse with preexisting cardiomyocytes, which stimulates cardiomyocyte cell cycle entry and likely proliferation, instead of directly differentiating into cardiomyocytes. Our findings provide evidence that cardiac SP cells contribute to endogenous cardiac regeneration through cardiomyocyte fusion.

scholarly journals Profiling proliferative cells and their progeny in damaged murine hearts

2018 ◽  
Vol 115 (52) ◽  
pp. E12245-E12254 ◽  
Author(s):  
Kai Kretzschmar ◽  
Yorick Post ◽  
Marie Bannier-Hélaouët ◽  
Andrea Mattiotti ◽  
Jarno Drost ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Function ◽  
Cardiac Fibroblasts ◽  
Cardiac Injury ◽  
Cardiac Regeneration ◽  
Cell Types ◽  
Postnatal Growth ◽  
Lineage Tracing ◽  
Genetic Lineage ◽  
Proliferating Cells

The significance of cardiac stem cell (CSC) populations for cardiac regeneration remains disputed. Here, we apply the most direct definition of stem cell function (the ability to replace lost tissue through cell division) to interrogate the existence of CSCs. By single-cell mRNA sequencing and genetic lineage tracing using two Ki67 knockin mouse models, we map all proliferating cells and their progeny in homoeostatic and regenerating murine hearts. Cycling cardiomyocytes were only robustly observed in the early postnatal growth phase, while cycling cells in homoeostatic and damaged adult myocardium represented various noncardiomyocyte cell types. Proliferative postdamage fibroblasts expressing follistatin-like protein 1 (FSTL1) closely resemble neonatal cardiac fibroblasts and form the fibrotic scar. Genetic deletion of Fstl1 in cardiac fibroblasts results in postdamage cardiac rupture. We find no evidence for the existence of a quiescent CSC population, for transdifferentiation of other cell types toward cardiomyocytes, or for proliferation of significant numbers of cardiomyocytes in response to cardiac injury.

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.

Abstract 35: Enhanced Reprogramming of Human Fibroblasts into Cardiomyocytes Using Minimal Transcription Factors

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Yang Zhou ◽  
Sahar Alimohamadi ◽  
Jiandong Liu ◽  
Li Qian
Keyword(s):  
Transcription Factors ◽  
Disease Modeling ◽  
Human Fibroblasts ◽  
Cardiac Injury ◽  
Cardiac Regeneration ◽  
Clinical Applications ◽  
Significant Advance ◽  
Great Promise ◽  
Primary Fibroblasts ◽  
Core Components

The adult human heart has limited regenerative capacity and is thus an important target for novel regenerative approaches to replenish lost cardiomyocytes after cardiac injury. Cardiac reprogramming that converts fibroblasts to contractile induced cardiomyocytes (iCMs) by overexpressing cardiac lineage specific transcription factors holds great promise as an alternative approach for cardiac regeneration and disease modeling. Significant advance has been made to generate mouse iCMs; however, human iCM (hiCM) generation remains challenging and the yield is low for clinical applications. Here, we leveraged the knowledge that we learned from studying mouse iCM reprogramming to define the optimal condition for hiCM induction. We titrated the dosage of the human reprogramming factors systematically and surprisingly found the minimal core components GATA4, MEF2C and TBX5 were sufficient to induce cardiac fate in human primary fibroblasts. This is in sharp contrast to what has been reported in the literature. Subsequently, we cloned these three factors into a polycistronic vector separated by 2A peptides for defined ratio of protein expression. By optimizing the growth condition, we further improved the efficiency of hiCM reprogramming. Mechanistically, we found the balanced expression of this minimal combination of transcription factors with tailored microenvironment enhanced the establishment of cardiac program in non-myocytes. In sum, our study demonstrates that the use of a single vector with only three transcription factors simplifies generation and improves the yield of hiCMs for potential future clinical applications.

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.

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