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Establishing an In Vitro Model of Skeletal Muscle Development and Aging Using Human Stem Cells.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Establishing an In Vitro Model of Skeletal Muscle Development and Aging Using Human Stem Cells./
Author:	Tey, Sin-Ruow.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2022,
Description:	233 p.
Notes:	Source: Dissertations Abstracts International, Volume: 83-11, Section: B.
Contained By:	Dissertations Abstracts International83-11B.
Subject:	Biology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=29209235
ISBN:	9798438748922

Establishing an In Vitro Model of Skeletal Muscle Development and Aging Using Human Stem Cells.
Tey, Sin-Ruow.

Establishing an In Vitro Model of Skeletal Muscle Development and Aging Using Human Stem Cells. - Ann Arbor : ProQuest Dissertations & Theses, 2022 - 233 p.

Source: Dissertations Abstracts International, Volume: 83-11, Section: B.

Thesis (Ph.D.)--The University of Wisconsin - Madison, 2022.

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

Stem cells have the unique properties of indefinite proliferation and multi-cell lineage differentiation, thereby providing a new unlimited cell resource for cellular modeling in basic and translational research. Myogenic progenitors can be successfully generated from human pluripotent stem cells (hPSCs) without genetic modifications by simulating small molecule signaling during embryonic myogenesis. The main objective of this thesis is to explore the utilizations of hPSC-derived myogenic progenitors as in vitro models to study skeletal muscle development and aging under natural and pathological conditions. First, we demonstrated that cell surface proteins can be used as markers to enrich and characterize hPSC-derived myogenic progenitors, as well as to identify new pathways through their involvements in myogenesis. We discovered that myotube formation was elevated in differentiated cultures of CD29+, CD56+, CD271+, and CD15- fractions, while myotube fusion and maturation were more prominent in the differentiated cultures from CD9+ and CD146+ fractions. We showed that CD271 expression is essential for terminal differentiation of hPSC-derived myogenic progenitors. Next, we developed in vitro culture systems of hPSC-derived myogenic progenitors to study age-related muscle degeneration. We found that supplementing hPSC-derived myogenic progenitors with aged rat sera impaired their self-renewal capacity and myotube formation potential. We identified indications of aberrant cell cycle events as the contributing factors to such aging phenotypes. Then, we replicated our work using supplementation of plasma from aged human donors. Our results confirmed that circulating factors in aged systemic biokinetics exerted inhibitory effects on viability and proliferation of hPSC-derived myogenic progenitors. We validated that treatment with plasma from healthy elders and patients of Alzheimer's disease during terminal differentiation led to abnormal morphological changes in myotubes: myotubes were enlarged and misshapen, and myonuclei were centrally aggregated. These observations again pointed towards disruption in cell cycle regulation. Lastly, we attempted to make new connections between age-related dysregulation of the balance of hypothalamus-pituitary-gonadal (HPG) axis, cell cycle aberrancy and muscle degeneration. We treated hPSC-derived myogenic progenitors with bioidentical HPG hormones at the concentrations reported in post-menopausal women to mimic endocrine dyscrasia. Our preliminary data suggests that age-specific imbalance of HPG hormones reduced expansion of hPSC-derived myogenic progenitors and contributed towards nuclear aggregation during myotube formation. Together, we successfully illustrated the feasibility of hPSC-derived culture systems as a powerful platform to investigate clinically relevant mechanisms of skeletal muscle development and aging.

ISBN: 9798438748922Subjects--Topical Terms:

522710
Biology.
Subjects--Index Terms:

In Vitro

Establishing an In Vitro Model of Skeletal Muscle Development and Aging Using Human Stem Cells.
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500 $a Source: Dissertations Abstracts International, Volume: 83-11, Section: B.
500 $a Advisor: Suzuki, Masatoshi.
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520 $a Stem cells have the unique properties of indefinite proliferation and multi-cell lineage differentiation, thereby providing a new unlimited cell resource for cellular modeling in basic and translational research. Myogenic progenitors can be successfully generated from human pluripotent stem cells (hPSCs) without genetic modifications by simulating small molecule signaling during embryonic myogenesis. The main objective of this thesis is to explore the utilizations of hPSC-derived myogenic progenitors as in vitro models to study skeletal muscle development and aging under natural and pathological conditions. First, we demonstrated that cell surface proteins can be used as markers to enrich and characterize hPSC-derived myogenic progenitors, as well as to identify new pathways through their involvements in myogenesis. We discovered that myotube formation was elevated in differentiated cultures of CD29+, CD56+, CD271+, and CD15- fractions, while myotube fusion and maturation were more prominent in the differentiated cultures from CD9+ and CD146+ fractions. We showed that CD271 expression is essential for terminal differentiation of hPSC-derived myogenic progenitors. Next, we developed in vitro culture systems of hPSC-derived myogenic progenitors to study age-related muscle degeneration. We found that supplementing hPSC-derived myogenic progenitors with aged rat sera impaired their self-renewal capacity and myotube formation potential. We identified indications of aberrant cell cycle events as the contributing factors to such aging phenotypes. Then, we replicated our work using supplementation of plasma from aged human donors. Our results confirmed that circulating factors in aged systemic biokinetics exerted inhibitory effects on viability and proliferation of hPSC-derived myogenic progenitors. We validated that treatment with plasma from healthy elders and patients of Alzheimer's disease during terminal differentiation led to abnormal morphological changes in myotubes: myotubes were enlarged and misshapen, and myonuclei were centrally aggregated. These observations again pointed towards disruption in cell cycle regulation. Lastly, we attempted to make new connections between age-related dysregulation of the balance of hypothalamus-pituitary-gonadal (HPG) axis, cell cycle aberrancy and muscle degeneration. We treated hPSC-derived myogenic progenitors with bioidentical HPG hormones at the concentrations reported in post-menopausal women to mimic endocrine dyscrasia. Our preliminary data suggests that age-specific imbalance of HPG hormones reduced expansion of hPSC-derived myogenic progenitors and contributed towards nuclear aggregation during myotube formation. Together, we successfully illustrated the feasibility of hPSC-derived culture systems as a powerful platform to investigate clinically relevant mechanisms of skeletal muscle development and aging.
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650 4 $a Cellular biology. $3 3172791
650 4 $a Histology. $3 641250
650 4 $a Bioinformatics. $3 553671
650 4 $a Aging. $3 543123
653 $a In Vitro
653 $a Skeletal muscle
653 $a Human stem cells
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690 $a 0379
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710 2 $a The University of Wisconsin - Madison. $b Comparative Biomedical Science. $3 3178809
773 0 $t Dissertations Abstracts International $g 83-11B.
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792 $a 2022
793 $a English
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