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Renewal of intestinal stem cells lacking intrinsic survival program requires microbiome and immune signaling input

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TitleInfo
Title
Renewal of intestinal stem cells lacking intrinsic survival program requires microbiome and immune signaling input
Name (type = personal)
NamePart (type = family)
Zhang
NamePart (type = given)
Xiao
NamePart (type = date)
1985
DisplayForm
Zhang, Xiao, 1985-
Role
RoleTerm (authority = RULIB); (type = text)
author
Name (type = personal)
NamePart (type = family)
Friedman
NamePart (type = given)
Wilma
DisplayForm
Wilma Friedman
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
chair
Name (type = corporate)
NamePart
Rutgers University
Role
RoleTerm (authority = RULIB)
degree grantor
Name (type = corporate)
NamePart
Graduate School - Newark
Role
RoleTerm (authority = RULIB)
school
TypeOfResource
Text
Genre (authority = marcgt)
theses
OriginInfo
DateCreated (encoding = w3cdtf); (keyDate = yes); (qualifier = exact)
2020
DateOther (qualifier = exact); (type = degree)
2020-05
Language
LanguageTerm (authority = ISO 639-3:2007); (type = text)
English
Abstract (type = abstract)
Being one important part of the digestive system, the intestine is responsible for nutrient uptake and for establishing a critical barrier against luminal insults from harsh chemicals or pathogens. Both functions are vital for the survival of the host. Strictly defined architecture of intestinal epithelial cells and the gradient of signaling cues along the villus-crypt axis ensure the maintenance of adult intestinal stem cells, as well as proper regeneration and differentiation of all intestinal epithelial cell types. The Rho family small GTPase Cdc42 controls the proper division of intestinal stem cells and affects subsequent fate-determination of the progenitor cells. How the intestinal epithelium maintains homeostasis and regenerative capacity during constant exposure to genotoxic and pathogenic insults is unclear. We found that ex vivo survival and clonogenicity of intestinal stem cells (ISCs)strictly required Cdc42-mediated response, and Cdc42-deficient enteroids underwent rapid apoptosis. Mechanistically, Cdc42 engaged EGFR and enabled MAPK signaling. Accordingly, mice engineered to have boosted Cdc42-MAPK signaling in ISCs showed enhanced regeneration and were protected from epithelial injury. However, mice with Cdc42-deficient epithelium were viable and maintained functional homeostasis. An ex vivo screen uncovered that a number of inflammatory cytokines restored growth of Cdc42-deficient enteroids. Indeed, intestinal regeneration in mice lacking epithelial Cdc42 was compromised when cytokine-signaling or microbiota sensing was abolished. Antibiotic treatment, IL-22 deficiency, or Stat3 blockage compromised epithelial survival and injury-induced regeneration in mice lacking epithelial Cdc42. Data from this thesis shed lights on how ISC-intrinsic survival programs collaborate with signals from immune and microbiome compartments to provide non-redundant layers of protection for epithelial integrity. We conclude that signaling inputs from microbiome and lamina propria lymphocytes facilitate survival of ISCs with defective survival program. These results suggest that activation of specific epithelial extrinsic signals may benefit intestinal mucosal regeneration in hosts with diminished survival program such as during severe genotoxic or pathogenic injuries.
Subject (authority = local)
Topic
Stem cells
Subject (authority = RUETD)
Topic
Biology
RelatedItem (type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier (type = RULIB)
ETD
RelatedItem (type = host)
TitleInfo
Title
Graduate School - Newark Electronic Theses and Dissertations
Identifier (type = local)
rucore10002600001
Identifier
ETD_10885
Identifier (type = doi)
doi:10.7282/t3-003d-wh71
PhysicalDescription
Form (authority = gmd)
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application/pdf
InternetMediaType
text/xml
Extent
1 online resource (xii, 226 pages)
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references
Location
PhysicalLocation (authority = marcorg); (displayLabel = Rutgers, The State University of New Jersey)
NjNbRU
Genre (authority = ExL-Esploro)
ETD doctoral
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Rights

RightsDeclaration (ID = rulibRdec0006)
The author owns the copyright to this work.
RightsHolder (type = personal)
Name
FamilyName
Zhang
GivenName
Xiao
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2020-04-29 14:35:16
AssociatedEntity
Name
Xiao Zhang
Role
Copyright holder
Affiliation
Rutgers University. Graduate School - Newark
AssociatedObject
Type
License
Name
Author Agreement License
Detail
I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
RightsEvent
Type
Embargo
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2020-05-31
DateTime (encoding = w3cdtf); (qualifier = exact); (point = end)
2022-05-31
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after May 31st, 2022.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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Technical

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windows xp
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2020-04-29T17:45:49
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2020-04-30T13:06:53
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