Bone marrow transplant and stem cell regeneration presented at Medical Research Conference Oct. 2011

Bone marrow stem cells and bone marrow transplants were the topics of the October 2011 Medical Research Conference.  Drs. Benny Chen and John Chute presented their latest findings on T cells and bone marrow stem cell regeneration and renewal.

Memory Loss Prevents Graft-versus-Host Disease

Benny Chen, MD, assistant professor of medicine (Cellular Therapy), began his talk by illuminating the many barriers clinicians face performing autonomous bone marrow transplant. Like organ transplantation, there is a risk of rejection in stem cell replantation.  Moreover, stem cell transplants can cause the graft-versus-host disease (GVHD), which was a major barrier to stem cell research 40 years ago. Though technology has improved, GVHD is still a severe complication that takes the life of half its victims. T cells, which Chen calls “the double-edge sword” of stem cell transplantation, can cause GVHD.  But clinical studies have also shown T cells and anti-infective and anti-tumor problems, which begs the question: How can you promote the immunity benefits of T cells without causing GVHD? At the same time Chen was exploring the two-sided nature of T cells, he was also looking at cord blood transplantation. He found that GVHD was less prevalent in this population, which led to a hypothesis that naïve T cells induce less GVHD than memory T cells. But research proved opposite: naïve T cells have never encountered antigens, thus almost always induced GVHD. Subsequent experiments shows that memory T cells react to antigens but do not induce GVHD, but the response to antigens quickly diminished,  “T Cells lose allo-reacticty over time upon transfer into allogeneic recipients,” said Chen. Now, Chen is trying to translate his findings to the clinic.

Hematopoietic Stem Cell Regeneration: Novel Mechanism and Therapeutic Targeting

John Chute, MD, professor of medicine (Cellular Therapy), works on the signaling processes involved in stem cell renewal. Most know that hematopoietic stem cells can self-renew and regenerate, but the mechanisms behind stem cell self-renewal and regeneration are not well known. Chute has studied whether vascular endothelial cells within the bone marrow microenvironment regulate these processes. Chute said the bone marrow is rich in vascular material – five years ago this vascular landscape was thought to be a passive environment. His lab’s hypothesis was that endothelial progenitor cells (EPC) were the antithesis of passive, and in fact, promote hematopoietic reconstitution. To test this theory, Chute embarked on a series of animal tests and models. It was soon apparent that EPC offered some element of stem sell renewal mechanism; mice given EPCs recovered faster, but if given an antibody that prevented EPCs from forming vessels, there was inhibition of hematopoietic recovery. Based on these findings, Chute’s lab performed a genomic analysis of human EPCs that support stem cell growth, and found a protein called pleiotrophin (PTN), which is expressed by neurons and had no known function in hematopoiesis.  To develop PTN’s role in a stem cell regeneration model, Chute’s lab gave mice a nearly lethal dose of radiation. Mice given PTN had accelerated regrowth by day fourteen. Chute said that PTN may inactivate phosphatase activity increasing the phosphorylation state of downstream targets as a means of regulating self-renewal. More recently, a post doctoral fellow in Chute’s laboratory, Dr. Heather Himburg, preliminarily demonstrated that antagonism of PTN inhibited acute myeloid leukemia growth in vivo. These collective data implicate PTN as an important regulator of normal and leukemic stem cells.