Genetic Lineage Tracing of Nonmyocyte Population by Dual Recombinases

Li, Yan; He, Lingjuan; Huang, Xiuzhen; Bhaloo, Shirin Issa; Zhao, Huan; Zhang, Shaohua; Pu, Wenjuan; Tian, Xueying; Li, Yang; Liu, Qiaozhen; Yu, Wei; Zhang, Libo; Liu, Xiuxiu; Li, Kuo; Tang, Juan; Zhang, Hui; Cai, Dongqing; Ralf, A. Hilger; Xu, Qingbo; Lui, Kathy O.; Zhou, Bin

doi:10.1161/circulationaha.118.034250

Cited by 172 publications

(144 citation statements)

References 51 publications

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“…However, the results of surface marker analyses should be interpreted with caution, as surface markers do not necessarily reflect cell function and as stem and/or progenitor cells can be highly plastic, and lineage-origin dependent. [30,31]…”

Section: Discussionmentioning

confidence: 99%

Step-Wise Chondrogenesis of Human Induced Pluripotent Stem Cells and Purification Via a Reporter Allele Generated by CRISPR-Cas9 Genome Editing

et al. 2018

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The differentiation of human induced pluripotent stem cells (hiPSCs) to prescribed cell fates enables the engineering of patient-specific tissue types, such as hyaline cartilage, for applications in regenerative medicine, disease modeling, and drug screening. In many cases, however, these differentiation approaches are poorly controlled and generate heterogeneous cell populations. Here we demonstrate cartilaginous matrix production in three unique hiPSC lines using a robust and reproducible differentiation protocol. To purify chondroprogenitors produced by this protocol, we engineered a COL2A1-GFP knock-in reporter hiPSC line by CRISPR-Cas9 genome editing. Purified chondroprogenitors demonstrated an improved chondrogenic capacity compared to unselected populations. The ability to enrich for chrondroprogenitors and generate homogenous matrix without contaminating cell types will be essential for regenerative and disease modeling applications.

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Section: Discussionmentioning

confidence: 99%

Step-Wise Chondrogenesis of Human Induced Pluripotent Stem Cells and Purification Via a Reporter Allele Generated by CRISPR-Cas9 Genome Editing

et al. 2018

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“…In recent years, there has been increased focus on accomplishing this by stimulating cardiomyocyte proliferation (Leach et al, 2017;Nakada et al, 2017). Moreover, recent evidence suggests that presumed cardiac progenitor cells, which were thought to have the advantage of giving rise to non-cardiomyocytes and cardiomyocytes, both of which are integral to normal cardiac function (Bollini et al, 2014;Garbern & Lee, 2013), are generally incapable of generating cardiomyocytes (Li et al, 2018;. Growing evidence has accumulated that Kit-expressing cells, the most extensively studied group of proposed cardiac progenitor cells, have a negligible contribution to endogenous cardiac regeneration (He et al, 2017;Sultana et al, 2015;.…”

Section: Discussionmentioning

confidence: 99%

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

Yellamilli

Ren

McElmurry

et al. 2019

Preprint

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The 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.

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“…An undisputed mechanism of action of CPC transplantation is their secretome reparative potential, which through acting in a paracrine manner improves cardiomyocyte survival [59][60][61], limits fibrosis [60][61][62], induces angiogenesis [59,61,63], and new cardiomyocyte formation [62][63][64] and restores cardiac function [57,59,60,[64][65][66] . Recently, considerable confusion has emanated over the significant cardiomyogenic potential of CPCs purported using Kitcre Knockin or dual recombinases-mediated cell tracking mice models [67][68][69].…”

Section: Introductionmentioning

confidence: 99%

Aged-senescent cells contribute to impaired heart regeneration

Lewis-McDougall

Ruchaya

Domenjo-Vila

et al. 2018

Preprint

105

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Aging leads to increased cellular senescence and is associated with decreased potency of tissue-specific stem/progenitor cells. Here we have done an extensive analysis of cardiac progenitor cells (CPCs) isolated from human subjects with cardiovascular disease (n=119), aged 32-86 years. In aged subjects (>74 years old) over half of CPCs are senescent (p16INK4A, SA-β-gal, DNA damage γH2AX, telomere length, Senescence-Associated Secretory Phenotype (SASP)), unable to replicate, differentiate, regenerate or restore cardiac function following transplantation into the infarcted heart. SASP factors secreted by senescent CPCs renders otherwise healthy CPCs to senescence. Elimination of senescent CPCs using senolytics abrogates the SASP and its debilitative effect in vitro. Global elimination of senescent cells in aged mice (INK-ATTAC or wildtype mice treated with D+Q senolytics) in vivo activates resident CPCs (0.23±0.06% vs. 0.01±0.01% vehicle; p<0.05) and increased the number of small, proliferating Ki67-, EdU-positive cardiomyocytes (0.25±0.07% vs. 0.03±0.03% vehicle; p<0.05). Therapeutic approaches that eliminate senescent cells may alleviate cardiac deterioration with aging and rejuvenate the regenerative capacity of the heart.

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Genetic Lineage Tracing of Nonmyocyte Population by Dual Recombinases

Cited by 172 publications

References 51 publications

Step-Wise Chondrogenesis of Human Induced Pluripotent Stem Cells and Purification Via a Reporter Allele Generated by CRISPR-Cas9 Genome Editing

Step-Wise Chondrogenesis of Human Induced Pluripotent Stem Cells and Purification Via a Reporter Allele Generated by CRISPR-Cas9 Genome Editing

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

Aged-senescent cells contribute to impaired heart regeneration

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