The major overall research interest of the Inlay lab is understanding the biology, origins, and therapeutic use of blood-forming stem cells, also referred to as hematopoietic stem cells, or HSCs. These stem cells are responsible for producing all the cell types of the blood system, which includes not only red blood cells but nearly all immune cells. HSCs reside primarily in the bone marrow and are the therapeutic cell in bone marrow transplantation (BMT), a procedure that can completely replace a patient’s diseased blood system with a healthy new one from a donor.

The early research in the Inlay lab focused on the embryonic origins of HSCs, and better understanding the developmental and genetic steps by which the first HSCs appear in the embryo. Our rationale was that by better understanding the natural mechanisms by which HSCs arise, we could recreate those steps in a dish to create new HSCs from pluripotent stem cells (PSCs) as a way to create an unlimited source of HSCs without needing to harvest from the bone marrow of a donor. Our work mainly focused on identifying which tissues in the embryo could produce HSCs, including both within the body of the embryo as well as regions that are part of the embryo but outside the main body. These tissues are called extra embryonic and include the placenta as well as the yolk sac. Our research implicated an important role for these extra-embryonic tissues in producing a precursor cell of the HSC, which are called pre-HSCs.

Another research area in the Inlay lab is on the role of the immune system in neurodegenerative diseases, particularly Alzheimer’s Disease (AD). In collaboration with Dr. Mathew Blurton-Jones and Dr. Craig Walsh, we investigated the role of adaptive immune cells such as B and T lymphocytes and discovered that in the absence of adaptive immunity, AD symptoms became more severe, suggesting that adaptive immune cells help to prevent the exacerbation of AD. Our work has also identified new markers to distinguish microglia from infiltrating immune cells, and helped to pinpoint the immune cells that surround the beta-amyloid plaques in a mouse model of AD.

Another research interest in the lab is the autoimmune disease called idiopathic thromobcytopenic purpura, or ITP for short. ITP is a disease where the body produces antibodies against platelets, which lead to a decrease in platelet counts which can result in debilitating bleeding episodes. We generated a novel mouse model of ITP by activating a foreign antigen in platelets, to induce an autoimmune response against those platelets. We are exploring treatments for ITP using this mouse model.

The major current research of the lab is now focused on a disease called graft-versus-host disease (GvHD), a complication associated with bone marrow transplantation. In an allogeneic transplant (where the donor HSCs come from an individual that is not the patient), recipient antigen presenting cells will interact and subsequently activate donor T cells, which will then elicit an immune response. Activated donor T cells will then attack host tissues, primarily skin, liver, and gut, leading to a high rate of morbidity. Clinically, GvHD is treated by global administration of immunosuppressive glucocorticoids (GCs), which have unwanted side effects, and leave the patient susceptible to opportunistic infections. Despite the recommended GC regimen, many patients still succumb to GvHD related death, thus highlighting a need for improvement in transplant safety. In our lab, we developed a mouse model in which GvHD is reduced by treating donor cells with GCs prior to an allogeneic bone marrow transplant. A major goal of this project it to identify the role key players which drive this reduction of GvHD in our model.