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Crosstalk Between Granulocytes, Gut ...

Bowers, Emily.

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Crosstalk Between Granulocytes, Gut Microbes, Stem Cells, and the Bone Marrow Microenvironment.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Crosstalk Between Granulocytes, Gut Microbes, Stem Cells, and the Bone Marrow Microenvironment./
Author:	Bowers, Emily.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2018,
Description:	103 p.
Notes:	Source: Dissertations Abstracts International, Volume: 80-07, Section: B.
Contained By:	Dissertations Abstracts International80-07B.
Subject:	Cellular biology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=11006838
ISBN:	9780438594333

Crosstalk Between Granulocytes, Gut Microbes, Stem Cells, and the Bone Marrow Microenvironment.
Bowers, Emily.

Crosstalk Between Granulocytes, Gut Microbes, Stem Cells, and the Bone Marrow Microenvironment. - Ann Arbor : ProQuest Dissertations & Theses, 2018 - 103 p.

Source: Dissertations Abstracts International, Volume: 80-07, Section: B.

Thesis (Ph.D.)--University of Michigan, 2018.

This item must not be added to any third party search indexes.

The bone marrow (BM) is the main site of hematopoiesis in mammals and it is here that hematopoietic stem and progenitor cells proliferate and differentiate to produce all the mature cells of the blood. The BM also contains several non-hematopoietic stromal populations and these, along with hematopoietic cells and signals emanating from outside the bone marrow, communicate to regulate the production of mature cells. In this thesis I describe two two novel mechanisms of this intricate regulation: 1) granulocytes crosstalk with BM endothelial cells to promote regeneration following bone marrow injury; and 2) neonatal gut microbes can regulate the proliferation and lineage commitment of hematopoietic stem cells (HSCs) in the BM via long distance communication. Previous studies demonstrated that vascular regeneration was a necessary precedent for the restoration of functional hematopoiesis following BM injury. While studying the mechanisms that regulate vascular recovery, we discovered that adoptive transfer of granulocytes into recipients undergoing bone marrow transplant (BMT) led to increased recovery and function of the BM vasculature, faster recovery of hematopoietic cells in the peripheral blood, and overall increased survival of transplant recipients. A screen of BM granulocytes for angiogenic factors identified TNFα as a potential candidate for the regenerative phenotype. Genetic studies using Tnfα -/- granulocytes and TNFα receptor null recipients validated granulocyte-derived TNFα as a newly discovered regulator of vascular regeneration. Concurrent to this research we also discovered a new role for the gut microbiota in regulating hematopoiesis. We discovered this by initially testing whether neonatal microbes could expand granulocyte numbers in the BM; as a connection between gut microbes during neonatal development and the expansion of BM granulocytes had been previously described. Surprisingly, we did not observe any difference in granulocyte numbers when comparing germ-free and specific pathogen free (SPF) neonates. However, when analyzing the function of the HSCs in these two groups, we found reduced proliferation and increased production of myeloid and T-cells in SPF neonates when compared to their germ-free counterparts. When germ-free neonates were fostered with a SPF dam or when neonatal (but not adult) gut microbiota were adoptively transferred into adult germ-free recipients, these same HSC phenotypes were observed, suggesting that manipulation of the composition of the gut microbiota is capable of influencing hematopoiesis in the BM at all stages of development. Taking both of these projects together, these results reveal that granulocytes and gut microbes can regulate hematopoiesis during homeostasis and regeneration.

ISBN: 9780438594333Subjects--Topical Terms:

3172791
Cellular biology.

Crosstalk Between Granulocytes, Gut Microbes, Stem Cells, and the Bone Marrow Microenvironment.
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500 $a Advisor: Maillard, Ivan Patrick;Nunez, Gabriel.
502 $a Thesis (Ph.D.)--University of Michigan, 2018.
506 $a This item must not be added to any third party search indexes.
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520 $a The bone marrow (BM) is the main site of hematopoiesis in mammals and it is here that hematopoietic stem and progenitor cells proliferate and differentiate to produce all the mature cells of the blood. The BM also contains several non-hematopoietic stromal populations and these, along with hematopoietic cells and signals emanating from outside the bone marrow, communicate to regulate the production of mature cells. In this thesis I describe two two novel mechanisms of this intricate regulation: 1) granulocytes crosstalk with BM endothelial cells to promote regeneration following bone marrow injury; and 2) neonatal gut microbes can regulate the proliferation and lineage commitment of hematopoietic stem cells (HSCs) in the BM via long distance communication. Previous studies demonstrated that vascular regeneration was a necessary precedent for the restoration of functional hematopoiesis following BM injury. While studying the mechanisms that regulate vascular recovery, we discovered that adoptive transfer of granulocytes into recipients undergoing bone marrow transplant (BMT) led to increased recovery and function of the BM vasculature, faster recovery of hematopoietic cells in the peripheral blood, and overall increased survival of transplant recipients. A screen of BM granulocytes for angiogenic factors identified TNFα as a potential candidate for the regenerative phenotype. Genetic studies using Tnfα -/- granulocytes and TNFα receptor null recipients validated granulocyte-derived TNFα as a newly discovered regulator of vascular regeneration. Concurrent to this research we also discovered a new role for the gut microbiota in regulating hematopoiesis. We discovered this by initially testing whether neonatal microbes could expand granulocyte numbers in the BM; as a connection between gut microbes during neonatal development and the expansion of BM granulocytes had been previously described. Surprisingly, we did not observe any difference in granulocyte numbers when comparing germ-free and specific pathogen free (SPF) neonates. However, when analyzing the function of the HSCs in these two groups, we found reduced proliferation and increased production of myeloid and T-cells in SPF neonates when compared to their germ-free counterparts. When germ-free neonates were fostered with a SPF dam or when neonatal (but not adult) gut microbiota were adoptively transferred into adult germ-free recipients, these same HSC phenotypes were observed, suggesting that manipulation of the composition of the gut microbiota is capable of influencing hematopoiesis in the BM at all stages of development. Taking both of these projects together, these results reveal that granulocytes and gut microbes can regulate hematopoiesis during homeostasis and regeneration.
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