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Stem Cell-Based Modeling of Early Hu...

Xue, Xufeng.

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Stem Cell-Based Modeling of Early Human Neural Development.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Stem Cell-Based Modeling of Early Human Neural Development./
作者:	Xue, Xufeng.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2020,
面頁冊數:	132 p.
附註:	Source: Dissertations Abstracts International, Volume: 81-11, Section: B.
Contained By:	Dissertations Abstracts International81-11B.
標題:	Biomedical engineering. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28006607
ISBN:	9798643185703

Stem Cell-Based Modeling of Early Human Neural Development.
Xue, Xufeng.

Stem Cell-Based Modeling of Early Human Neural Development. - Ann Arbor : ProQuest Dissertations & Theses, 2020 - 132 p.

Source: Dissertations Abstracts International, Volume: 81-11, Section: B.

Thesis (Ph.D.)--University of Michigan, 2020.

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

Neurulation is a key embryonic developmental process that gives rise to the formation of the neural tube (NT), the precursor structure that eventually develops into the central nervous system (CNS). Understanding the molecular mechanisms and morphogenetic events underlying human neurulation is important for the prevention and treatment of neural tube defects (NTDs) and neurodevelopmental disorders. However, animal models are limited in revealing many fundamental aspects of neurulation that are unique to human CNS development. Furthermore, the technical difficulty and ethical constraint in accessing neurulation-stage human embryos have significantly limited experimental investigations of early human CNS development.In this dissertation, I leveraged the developmental potential and self-organizing property of human pluripotent stem cells (hPSCs) in conjunction with 2D and 3D bioengineering tools to achieve the development of spatially patterned multicellular tissues that mimic certain aspects of the early human neurulation, including neural induction and dorsal-ventral (DV) patterning of NT.In the first section, I report a micropatterned hPSC-based neuroectoderm model, wherein pre-patterned geometrical confinement induces emergent patterning of neuroepithelial (NE) and neural plate border (NPB) cells, mimicking neuroectoderm patterning during early neurulation. My data support the hypothesis that in this hPS cell-based neuroectoderm patterning model, two tissue-scale morphogenetic signals, cell shape and cytoskeletal contractile force, instruct NE / NPB patterning via BMP-SMAD signaling. This work provides evidence of tissue mechanics-guided neuroectoderm patterning and establishes a tractable model to study signaling crosstalk involving both biophysical and biochemical determinants in neuroectoderm patterning.In the second section, I report a human NT development model, in which NT-like tissues, termed NE cysts, are generated in a bioengineered neurogenic environment through self-organization of hPSCs. DV patterning of NE cysts is achieved using retinoic acid and/or Sonic Hedgehog, featuring sequential emergence of the ventral floor plate, p3 and pMN domains in discrete, adjacent regions and dorsal territory that is progressively restricted to the opposite dorsal pole.These hPS cell-based in vitro models are important alternatives to animal models to study the self-organizing principles involved in autonomous patterning during human neurulation. These models could also be leveraged for developing high-throughput toxicological studies and drug screening platforms for prevention and treatment of neural tube defects.

ISBN: 9798643185703Subjects--Topical Terms:

535387
Biomedical engineering.
Subjects--Index Terms:

Human pluripotent stem cells

Stem Cell-Based Modeling of Early Human Neural Development.
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520 $a Neurulation is a key embryonic developmental process that gives rise to the formation of the neural tube (NT), the precursor structure that eventually develops into the central nervous system (CNS). Understanding the molecular mechanisms and morphogenetic events underlying human neurulation is important for the prevention and treatment of neural tube defects (NTDs) and neurodevelopmental disorders. However, animal models are limited in revealing many fundamental aspects of neurulation that are unique to human CNS development. Furthermore, the technical difficulty and ethical constraint in accessing neurulation-stage human embryos have significantly limited experimental investigations of early human CNS development.In this dissertation, I leveraged the developmental potential and self-organizing property of human pluripotent stem cells (hPSCs) in conjunction with 2D and 3D bioengineering tools to achieve the development of spatially patterned multicellular tissues that mimic certain aspects of the early human neurulation, including neural induction and dorsal-ventral (DV) patterning of NT.In the first section, I report a micropatterned hPSC-based neuroectoderm model, wherein pre-patterned geometrical confinement induces emergent patterning of neuroepithelial (NE) and neural plate border (NPB) cells, mimicking neuroectoderm patterning during early neurulation. My data support the hypothesis that in this hPS cell-based neuroectoderm patterning model, two tissue-scale morphogenetic signals, cell shape and cytoskeletal contractile force, instruct NE / NPB patterning via BMP-SMAD signaling. This work provides evidence of tissue mechanics-guided neuroectoderm patterning and establishes a tractable model to study signaling crosstalk involving both biophysical and biochemical determinants in neuroectoderm patterning.In the second section, I report a human NT development model, in which NT-like tissues, termed NE cysts, are generated in a bioengineered neurogenic environment through self-organization of hPSCs. DV patterning of NE cysts is achieved using retinoic acid and/or Sonic Hedgehog, featuring sequential emergence of the ventral floor plate, p3 and pMN domains in discrete, adjacent regions and dorsal territory that is progressively restricted to the opposite dorsal pole.These hPS cell-based in vitro models are important alternatives to animal models to study the self-organizing principles involved in autonomous patterning during human neurulation. These models could also be leveraged for developing high-throughput toxicological studies and drug screening platforms for prevention and treatment of neural tube defects.
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