Author's School

Graduate School of Arts & Sciences

Author's Department/Program

Biology and Biomedical Sciences: Developmental, Regenerative and Stem Cell Biology

Language

English (en)

Date of Award

Spring 3-12-2013

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Kyunghee Choi

Abstract

Although the physiological role of stem cells in generating and maintaining a functional biological system is widely appreciated, very little is known about the behavior of these cells in pathological conditions. If and how these primitive cells are affected by a disease process or may contribute to the disease process has not been adequately explored. We have studied the Hematopoietic System, with particular emphasis on Hematopoietic Stem Cells: HSCs) and Progenitors, in a spontaneous murine autoimmune arthritis model. We found that these mice have a systemic increase in myeloid cells, which correlated with an increased frequency of granulocyte-monocyte progenitors relative to other committed progenitors in arthritic marrow. Gene expression analysis of uncommitted Kit+Sca1+Lin-: KSL) cells from arthritic bone marrow revealed increased expression of myeloid cell related transcripts at the expense of megakaryocyte and erythroid transcripts. In vitro, KSL cells from arthritic mice were markedly superior in generating myeloid cells, including osteoclasts. When KSL cells from arthritic and control mice were competitively transplanted arthritic KSL cells performed better in reconstituting the myeloid compartment. Sustained myeloid output in vivo was environment dependent since it was abolished in young recipients but sustained in old recipients. In these old recipients, enhanced myeloid output from arthritic KSL cells could be detected 6 months post transplantation suggesting that the myeloid primed state exists in the most primitive long term reconstituting HSC: LT-HSC) fraction of KSL cells. Consistent with this, we identify a "myeloid inflammatory signature" - defined by upregulation of S100a8, S100a9, Chi3l3 and SOCS3 transcripts - that is triggered not only in KSL cells but also to an even greater degree in prospectively sorted arthritic CD150+CD48-CD34-KSL LT-HSCs. Our results indicate that primitive uncommitted progenitors of arthritic mice are molecularly altered to have increased myeloid potential while preserving multipotentiality and self-renewal. Since myeloid cells are critical in the inflammation and destruction that accompany arthritis, our results further suggest that uncommitted progenitors adopt a pathologic state that favors disease persistence. Therefore we identify the apparent existence of "inflammatory stem cells". This has implications for our understanding of mechanisms driving chronicity of chronic diseases and the potential involvement of stem cells in the process.

Comments

Permanent URL: http://dx.doi.org/10.7936/K77S7KSB

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