Steven Highfill

E-mail: highf008@umn.edu

Thesis Advisor: Bruce Blazar

Year entered: 2004

Degrees received:
B.S., Biology, University of South Florida, Tampa, FL 2002

Honors and Awards:

• Childrens Cancer Research Fund (2005), “Multipotent Adult Progenitor Cells’ suppression of allogeneic T-cell response”
• Childrens Cancer Research Fund (2008), “Mesenchymal Stem Cell production of PGE2 has a positive influence on HSC homeostasis and engraftment”
• Childrens Cancer Research Fund (2009), Myeloid Derived suppressor Cells for graft-versus-host disease prevention”
• MICAB Student Travel Award (Fall 2008)

Committee’s:
MICaB Faculty Admissions Committee, 2008-2009

Thesis research:
One major goal of our laboratory is to develop novel, less toxic, cellular approaches to improve the outcome of bone marrow transplantation (BMT). Despite the many advances in the field over the past decade, BM graft failure and graft-versus-host disease remain as two major limitations to the procedure. We are employing the use of two distinct cell types to achieve this goal: Mesenchymal Stem Cells (MSC) and Multipotent Adult Progenitor Cells (MAPC). Both cell types can be harvested from the bone marrow using differing techniques, which leads to the outgrowth of different populations of cells. Both cell types express molecules known to foster BM engraftment, and both cell types have the ability to inhibit an allogeneic MLR in vitro, giving us precedence into examining these cells for in vivo engraftment promotion and inhibition of GvHD, respectively.

Dissertation Research Project 1: “Multipotent Progenitor cells inhibit allogeneic T cell responses.”
The majority of my dissertation research is focused on the development of novel cellular strategies to limit Graft-versus-Host Disease (GVHD) following allogeneic bone marrow transplantation. I utilize murine BMT model systems to test strategies which limit allogeneic T cell activation and proliferation. My findings were first to identify Multipotent Adult Progenitor Cells (MAPCs) as potent suppressors of T cells and the agent by which they elicit suppression. This was also the first definitive report showing localization of this type of suppressor cell to sites of allo-priming was necessary to ameliorate GVHD.

Dissertation Research Project 2: “Enhancement of Bone Marrow Engraftment using Mesenchymal Stem Cells.”
My thesis research also investigates the potential of murine mesenchymal stem cells (MSC) to promote BM engraftment and the mechanism by which this is done. We have found that BM-derived MSCs secrete large quantities of prostaglandin E2, and when injected into transplanted mice, they preferentially home to the bone marrow cavity. There, PGE2 has a positive influence on the proliferation and homeostasis of Hematopoietic Stem Cells (HSCs) that result in improved engraftment. These will be the first studies to elucidate the mechanism of action MSCs have on HSCs in terms of engraftment promotion.

Laboratory web site: http://www.med.umn.edu/peds/blazarlab/

Publications:

• Ryan M. Kelly, Steven L. Highfill, Angela-Panoskaltsis-Mortari, Patricia A. Taylor, Richard L. Boyd, Georg A. Holländer, and Bruce R. Blazar. “Keratinocyte Growth Factor and Androgen Blockade Work in Concert to Protect Against Conditioning Regimen-Induced Thymic Epithelial Damage and Enhance T-Cell Reconstitution Following Murine Bone Marrow Transplantation”, Blood. 111(12):5734-44..

• Steven L. Highfill, Ryan M. Kelly, Matthew J. O'Shaughnessy, Qing Zhou, Lily Xia, Angela Panoskaltsis-Mortari, Patricia A Taylor, Jakub Tolar, Bruce R. Blazar. “Multipotent Adult Progenitor Cells (MAPC) can suppress graft versus host disease via prostaglandin E2 synthesis and only if localized to sites of allopriming”, Blood, 2009; 114(3):693-701.

• Qing Zhou, Christoph Bucher, Meghan E Munger, Steven L Highfill, Jakub Tolar, David Munn, Bruce Levine, Daniel A Vallera, Brenda J Weigel, Bruce R Blazar. “Depletion of endogenous tumor-associated regulatory T cells improves the efficacy of adoptive cytotoxic T cell immunotherapy in murine acute myeloid leukemia”, Blood, 2009; 114(18):3793-802.