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Bioengineering Morphogenesis and Differentiation in Human Brain Organoids
Bioengineering Morphogenesis and Differentiation in Human Brain Organoids
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20260311091549.5
- ISBN
- 9798280719842
- DDC
- 611
- 서명/저자
- Bioengineering Morphogenesis and Differentiation in Human Brain Organoids / Ezekiel Benshirim
- 발행사항
- [Sl] : Harvard University, 2025
- 형태사항
- 1 electronic resource (235 pages)
- 주기사항
- Source: Dissertations Abstracts International, Volume: 86-12, Section: B.
- 주기사항
- Advisors: Arlotta, Paola Committee members: Lehtinen, Maria; Rubin, Lee; Tang, Xin; Koppes, Abigail.
- 학위논문주기
- - Ph.D. : Harvard University, 2025.
- 초록/해제
- 요약The developmental processes that give rise to the distinctive human cerebral cortex are experimentally inaccessible, and only partially recapitulated in animal models. Brain organoids derived from human stem cells offer a unique window into these events at the cellular level. However, organoids deviate from the single-lumen morphology and polarized tissue architecture of the embryonic cortex, which orchestrate cell-cell interactions critical for normal development in vivo. Here, I develop techniques for culturing 3D in vitro human organoid models of the cerebral cortex that maintain a single ventricle-like structure and display biomimetic polarization of the cortical neuroepithelium. I apply these models to investigate the role of tissue-level mechanical forces in balancing between proliferation and differentiation of neural stem cells. I find that manually inflating organoids by injection of biocompatible fluids to increase intraluminal pressure promotes the maintenance and expansion of endogenous-like tissue architecture. This injection protocol prolongs the survival of apicobasally polarized architecture from the previously reported maximum of 22 days in culture to at least 49 days, maintains this architecture as organoids grow to over a millimeter in diameter, and can preserve the overall single-lumen structure for up to three months. Leveraging the ability of this model to experimentally vary mechanical strain on human neuroepithelium-like tissue, I demonstrate that inflation of ventricular structures in organoids delays neurogenesis, favoring proliferative divisions of neural progenitors at the expense of differentiation. Conversely, pressure release is rapidly followed by an increase in neuronal differentiation. This finding suggests that mechanical forces naturally present in the early brain could play a key role in regulating the timing and extent of stem cell proliferation relative to differentiation, serving as a previously unrecognized driver of final cortex size and cellular composition. As a step towards future models that could enable experimental exposure of biomimetic human neuroepithelia to realistic polarized biochemical signals, I also completed the design and pilot experiments for a microfluidically perfused neural tube model. Together, my results show that organoid-derived neural stem cells retain the ability to form large-scale tissues with high fidelity to in vivo histology when provided with appropriate mechanical cues, and illustrate the potential for bioengineered brain models to investigate fundamental questions in developmental neurobiology.
- 언어주기
- English
- 일반주제명
- Developmental biology
- 일반주제명
- Neurosciences
- 일반주제명
- Physiology
- 키워드
- Neurobiology
- 키워드
- Embryonic cortex
- 기타저자
- Harvard University Biological and Biomedical Sciences
- 기본자료저록
- Dissertations Abstracts International. 86-12B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■006m o d
■007cr|nu||||||||
■020 ▼a9798280719842
■040 ▼aMiAaPQD▼beng▼cMiAaPQD▼erda
■082 ▼a611
■1001 ▼aBenshirim, Ezekiel▼eauthor.▼0(orcid)0000-0001-6865-9707
■24510▼aBioengineering Morphogenesis and Differentiation in Human Brain Organoids ▼cEzekiel Benshirim
■260 ▼a[Sl]▼bHarvard University▼c2025
■264 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2025
■300 ▼a1 electronic resource (235 pages)
■336 ▼atext▼btxt▼2rdacontent
■337 ▼acomputer▼bc▼2rdamedia
■338 ▼aonline resource▼bcr▼2rdacarrier
■500 ▼aSource: Dissertations Abstracts International, Volume: 86-12, Section: B.
■500 ▼aAdvisors: Arlotta, Paola Committee members: Lehtinen, Maria; Rubin, Lee; Tang, Xin; Koppes, Abigail.
■5021 ▼bPh.D.▼cHarvard University▼d2025.
■520 ▼aThe developmental processes that give rise to the distinctive human cerebral cortex are experimentally inaccessible, and only partially recapitulated in animal models. Brain organoids derived from human stem cells offer a unique window into these events at the cellular level. However, organoids deviate from the single-lumen morphology and polarized tissue architecture of the embryonic cortex, which orchestrate cell-cell interactions critical for normal development in vivo. Here, I develop techniques for culturing 3D in vitro human organoid models of the cerebral cortex that maintain a single ventricle-like structure and display biomimetic polarization of the cortical neuroepithelium. I apply these models to investigate the role of tissue-level mechanical forces in balancing between proliferation and differentiation of neural stem cells. I find that manually inflating organoids by injection of biocompatible fluids to increase intraluminal pressure promotes the maintenance and expansion of endogenous-like tissue architecture. This injection protocol prolongs the survival of apicobasally polarized architecture from the previously reported maximum of 22 days in culture to at least 49 days, maintains this architecture as organoids grow to over a millimeter in diameter, and can preserve the overall single-lumen structure for up to three months. Leveraging the ability of this model to experimentally vary mechanical strain on human neuroepithelium-like tissue, I demonstrate that inflation of ventricular structures in organoids delays neurogenesis, favoring proliferative divisions of neural progenitors at the expense of differentiation. Conversely, pressure release is rapidly followed by an increase in neuronal differentiation. This finding suggests that mechanical forces naturally present in the early brain could play a key role in regulating the timing and extent of stem cell proliferation relative to differentiation, serving as a previously unrecognized driver of final cortex size and cellular composition. As a step towards future models that could enable experimental exposure of biomimetic human neuroepithelia to realistic polarized biochemical signals, I also completed the design and pilot experiments for a microfluidically perfused neural tube model. Together, my results show that organoid-derived neural stem cells retain the ability to form large-scale tissues with high fidelity to in vivo histology when provided with appropriate mechanical cues, and illustrate the potential for bioengineered brain models to investigate fundamental questions in developmental neurobiology.
■546 ▼aEnglish
■590 ▼aSchool code: 0084
■650 4▼aDevelopmental biology
■650 4▼aNeurosciences
■650 4▼aPhysiology
■653 ▼aNeurobiology
■653 ▼aEmbryonic cortex
■653 ▼aTissue architecture
■653 ▼aNeural progenitors
■653 ▼aHuman neuroepithelia
■7102 ▼aHarvard University▼bBiological and Biomedical Sciences.▼edegree granting institution.
■7201 ▼aArlotta, Paola▼edegree supervisor.
■7730 ▼tDissertations Abstracts International▼g86-12B.
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17357830▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
