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Modeling the Development of Human At...

Lee, Jee Hoon.

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Modeling the Development of Human Atrial and Ventricular Cardiomyocyte Lineages from Human Pluripotent Stem Cells.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Modeling the Development of Human Atrial and Ventricular Cardiomyocyte Lineages from Human Pluripotent Stem Cells./
Author:	Lee, Jee Hoon.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2018,
Description:	145 p.
Notes:	Source: Dissertations Abstracts International, Volume: 80-06, Section: B.
Contained By:	Dissertations Abstracts International80-06B.
Subject:	Biology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10837256
ISBN:	9780438682504

Modeling the Development of Human Atrial and Ventricular Cardiomyocyte Lineages from Human Pluripotent Stem Cells.
Lee, Jee Hoon.

Modeling the Development of Human Atrial and Ventricular Cardiomyocyte Lineages from Human Pluripotent Stem Cells. - Ann Arbor : ProQuest Dissertations & Theses, 2018 - 145 p.

Source: Dissertations Abstracts International, Volume: 80-06, Section: B.

Thesis (Ph.D.)--University of Toronto (Canada), 2018.

This item must not be sold to any third party vendors.

The ability to direct the differentiation of human pluripotent stem cells (hPSCs) to the different cardiovascular lineages is a prerequisite to modeling specific forms of cardiovascular disease in vitro and for developing novel therapies to treat them. Here we have investigated the development of human atrial and ventricular lineages and demonstrated that retinoic acid (RA) signaling is critical for the atrial fate specification. Insights into the origin of RA signaling has led us to identify that the atrial and ventricular cardiomyocyte lineages develop from distinct mesoderm populations that are marked by the expression of RALDH2 and CD235a, respectively. The RALDH2+ cells give rise to highly enriched atrial cardiomyocytes in the presence of retinol, suggesting that these progenitors can both produce and respond to RA in an autocrine fashion. Analyses of derivative cardiomyocyte populations have demonstrated that the generation of highly enriched, functional cardiomyocyte subtypes depend on the appropriate patterning of early progenitor populations. Based on these findings, we have initiated two independent analytical approaches, the CD-antibody library screen and single cell RNA-seq (scRNA-seq) analyses, to gain better insights into these progenitor populations. Analyses from the antibody screen has identified a new cell surface marker CD324 that has uniquely marked the transition from CD235a+ mesoderm to the early NKX2-5+ cardiomyocyte progenitor stage. We hypothesize that CD324 expression marks the formation of the cardiac crescent-like population from hPSCs. From the same study, we have identified that NOTCH2 and -3 receptors are expressed on the ventricular but not atrial mesoderm populations, suggesting a lineage-specific role of this signaling pathway. Preliminary analyses of scRNA-seq study has also demonstrated heterogeneity within the ventricular progenitor population. Together, these findings provide novel insights into the earliest stage of human heart development that enable the generation of highly enriched cardiomyocyte subtypes for future therapeutic applications.

ISBN: 9780438682504Subjects--Topical Terms:

522710
Biology.

Modeling the Development of Human Atrial and Ventricular Cardiomyocyte Lineages from Human Pluripotent Stem Cells.
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520 $a The ability to direct the differentiation of human pluripotent stem cells (hPSCs) to the different cardiovascular lineages is a prerequisite to modeling specific forms of cardiovascular disease in vitro and for developing novel therapies to treat them. Here we have investigated the development of human atrial and ventricular lineages and demonstrated that retinoic acid (RA) signaling is critical for the atrial fate specification. Insights into the origin of RA signaling has led us to identify that the atrial and ventricular cardiomyocyte lineages develop from distinct mesoderm populations that are marked by the expression of RALDH2 and CD235a, respectively. The RALDH2+ cells give rise to highly enriched atrial cardiomyocytes in the presence of retinol, suggesting that these progenitors can both produce and respond to RA in an autocrine fashion. Analyses of derivative cardiomyocyte populations have demonstrated that the generation of highly enriched, functional cardiomyocyte subtypes depend on the appropriate patterning of early progenitor populations. Based on these findings, we have initiated two independent analytical approaches, the CD-antibody library screen and single cell RNA-seq (scRNA-seq) analyses, to gain better insights into these progenitor populations. Analyses from the antibody screen has identified a new cell surface marker CD324 that has uniquely marked the transition from CD235a+ mesoderm to the early NKX2-5+ cardiomyocyte progenitor stage. We hypothesize that CD324 expression marks the formation of the cardiac crescent-like population from hPSCs. From the same study, we have identified that NOTCH2 and -3 receptors are expressed on the ventricular but not atrial mesoderm populations, suggesting a lineage-specific role of this signaling pathway. Preliminary analyses of scRNA-seq study has also demonstrated heterogeneity within the ventricular progenitor population. Together, these findings provide novel insights into the earliest stage of human heart development that enable the generation of highly enriched cardiomyocyte subtypes for future therapeutic applications.
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