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Human Umbilical Cord Blood is a Func...

Kim, Jieun.

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Human Umbilical Cord Blood is a Functionally and Developmentally Relevant Source of Macrophages with Therapeutic Potential.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Human Umbilical Cord Blood is a Functionally and Developmentally Relevant Source of Macrophages with Therapeutic Potential./
Author:	Kim, Jieun.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2018,
Description:	172 p.
Notes:	Source: Dissertations Abstracts International, Volume: 80-02, Section: B.
Contained By:	Dissertations Abstracts International80-02B.
Subject:	Biomedical engineering. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10748768
ISBN:	9780438187450

Human Umbilical Cord Blood is a Functionally and Developmentally Relevant Source of Macrophages with Therapeutic Potential.
Kim, Jieun.

Human Umbilical Cord Blood is a Functionally and Developmentally Relevant Source of Macrophages with Therapeutic Potential. - Ann Arbor : ProQuest Dissertations & Theses, 2018 - 172 p.

Source: Dissertations Abstracts International, Volume: 80-02, Section: B.

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

This item is not available from ProQuest Dissertations & Theses.

Recently, two major themes have emerged in the field of macrophage biology: developmental origin and self-renewal potential. While the overlap between these two themes remains elusive, recent mouse data demonstrate distinct functions between macrophages generated via primitive hematopoiesis versus definitive hematopoiesis. As for self-renewal potential, terminally differentiated mouse macrophages proliferate via a self-renewal gene regulatory network. Yet, how these observations are associated with each other, and how they extend to human macrophages remain poorly understood. Herein, we hypothesize that human umbilical cord blood (hUCB) is an alternative source of macrophages distinct from human peripheral blood mononuclear cell-derived macrophages (hPBMC MФ). First, we demonstrate that macrophage-specific functions, such as phagocytosis, reactive oxygen species (ROS) production, and cytokine secretion are comparable between hPBMC MФ and hUCB MФ. In contrast, hUCB MФ are distinct from hPBMC MФ with respect to primitive hematopoiesis and self-renewal-associated genes. We highlight significantly stronger correlations between these genes in hUCB MФ, by disrupting their gene regulatory network using siRNA. These data support the use of hUCB as a distinct source of macrophages, and suggest that the developmental origin of human macrophages may influence their gene regulatory network and consequent cellular responses. Second, noting that cardiac resident macrophages are closely associated with regenerative potential, we explore the use of this new source of human macrophages, and engineer a cardiac tissue to develop a model of cardiac disease. Specifically, we develop an engineered heart tissue (EHT) model based on human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) as an experimental platform where hUCB MФ activities can be introduced. This reductionist approach allows the exploration of functional outputs of hPSC-CMs mimicking myocardial infarction in vitro. Our work demonstrates that human mimetic EHT can be developed and engineered to provide an experimental platform to investigate and harness immune modulation of ontologically relevant macrophages, presenting highly translatable therapeutic potential of hUCB MФ. Overall, this thesis provides an in-depth functional characterization of hUCB MФ and introduces a new model technology for exploring therapeutic utility of this cell source.

ISBN: 9780438187450Subjects--Topical Terms:

535387
Biomedical engineering.

Human Umbilical Cord Blood is a Functionally and Developmentally Relevant Source of Macrophages with Therapeutic Potential.
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500 $a Publisher info.: Dissertation/Thesis.
500 $a Advisor: Zandstra, Peter W.
502 $a Thesis (Ph.D.)--University of Toronto (Canada), 2018.
506 $a This item is not available from ProQuest Dissertations & Theses.
506 $a This item must not be sold to any third party vendors.
520 $a Recently, two major themes have emerged in the field of macrophage biology: developmental origin and self-renewal potential. While the overlap between these two themes remains elusive, recent mouse data demonstrate distinct functions between macrophages generated via primitive hematopoiesis versus definitive hematopoiesis. As for self-renewal potential, terminally differentiated mouse macrophages proliferate via a self-renewal gene regulatory network. Yet, how these observations are associated with each other, and how they extend to human macrophages remain poorly understood. Herein, we hypothesize that human umbilical cord blood (hUCB) is an alternative source of macrophages distinct from human peripheral blood mononuclear cell-derived macrophages (hPBMC MФ). First, we demonstrate that macrophage-specific functions, such as phagocytosis, reactive oxygen species (ROS) production, and cytokine secretion are comparable between hPBMC MФ and hUCB MФ. In contrast, hUCB MФ are distinct from hPBMC MФ with respect to primitive hematopoiesis and self-renewal-associated genes. We highlight significantly stronger correlations between these genes in hUCB MФ, by disrupting their gene regulatory network using siRNA. These data support the use of hUCB as a distinct source of macrophages, and suggest that the developmental origin of human macrophages may influence their gene regulatory network and consequent cellular responses. Second, noting that cardiac resident macrophages are closely associated with regenerative potential, we explore the use of this new source of human macrophages, and engineer a cardiac tissue to develop a model of cardiac disease. Specifically, we develop an engineered heart tissue (EHT) model based on human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) as an experimental platform where hUCB MФ activities can be introduced. This reductionist approach allows the exploration of functional outputs of hPSC-CMs mimicking myocardial infarction in vitro. Our work demonstrates that human mimetic EHT can be developed and engineered to provide an experimental platform to investigate and harness immune modulation of ontologically relevant macrophages, presenting highly translatable therapeutic potential of hUCB MФ. Overall, this thesis provides an in-depth functional characterization of hUCB MФ and introduces a new model technology for exploring therapeutic utility of this cell source.
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