Biomedical Sciences ETDs

Publication Date

Fall 10-18-2018

Abstract

The maintenance of the hematopoietic stem and progenitor cell (HSPC) population is critical to sustaining the adult blood and immune system throughout an organism’s lifespan. The bone marrow microenvironment plays a key role in the regulation of HSPC maintenance and functions. Previous work from our lab has identified the tetraspanin CD82 as an important modulator of HSPC interactions with the bone marrow niche. However, the mechanisms as to how CD82 contributes to the maintenance, trafficking and retention of HSPCs with the niche remained unclear. First, we investigated how CD82 promotes HSPC quiescence, homing and engraftment using a global CD82 knock out (CD82KO) mouse model. Our data demonstrate that CD82 promotes the maintenance of the long-term HSC population within the bone marrow through increased quiescence. Additionally, we demonstrate that CD82KO HSPCs display reduced bone marrow homing and engraftment, identifying a key role for CD82 in these processes. We demonstrate that Rac1 is hyperactivated in the CD82KO HSPCs and inhibition directed to Rac1 restored HSPC homing and migration. We also identified CD82 as a novel regulator of HSPC mobilization. Our data demonstrate that CD82 promotes bone marrow retention, finding increased blood mobilization in the CD82KO mice. Further studies identified the S1PR1 as a key component of CD82-mediated mobilization. Taken together, these data provide evidence that CD82 is a critical regulator of HSPC quiescence, homing, engraftment and mobilization. More importantly, these studies identify CD82 as a potential novel molecular target to enhance HSPC transplantation therapies for treatment of hematological and non-hematological disorders.

Keywords

Hematopoietic stem cells, hematopoietic stem and progenitor cells, CD82, Rac1, tetraspanin, S1PR1

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Jennifer Gillette, PhD

Second Committee Member

Angela Wandinger-Ness, PhD

Third Committee Member

Scott Ness, PhD

Fourth Committee Member

Nancy Kanagy, PhD

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