EITS Student Isha Khan Publishes Exciting Research on the Role of AHR in Human Hematopoiesis

November 28, 2023

Environmental and Integrative Toxicological Sciences (EITS) graduate student, Isha Khan, in collaboration with a team of scientists including Peer Karmaus, Anthony Bach, Robert Crawford and Norbert Kaminski, recently published exciting research on the role of the aryl hydrocarbon receptor (AHR) in human hematopoiesis, the process by which blood cells are formed. The paper, “An in vitro model of human hematopoiesis identifies a regulatory role for the aryl hydrocarbon receptor,” was published in October 2023 in the journal, Blood Advances.

Human hematopoietic stem cells undergo successive rounds of differentiation and give rise to different types of blood cells, including the immune cells, in the body. A good balance between the different branches of the hematopoietic cell lineages is necessary for healthy living. The aryl hydrocarbon receptor (AHR) is a protein that regulates gene expression in cells and has important physiological functions. However, the role of AHR in human hematopoiesis is not well understood. Khan’s research works to explain the role played by AHR in altering human hematopoietic stem and progenitor cell (HSPC) differentiation.

Khan recognized that current in vitro models to study concurrent immune cell development from hematopoietic stem cells in a single system were scarce. He took this opportunity to identify and characterize, using single cell modalities, a model of human hematopoiesis in an in vitro platform that, without the need for any other supporting cells, allows the development of most major immune cell types, except for T cells. Using this model, Khan demonstrated that 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD), a highly potent activator of the AHR, even at very low concentrations, skews human hematopoietic stem and progenitor cell differentiation towards certain immune cell lineages, specifically granulocytes and monocytes, at the expense of other immune lineages such as lymphoid progenitors, B lymphocytes, dendritic cells, and megakaryocytes. This is an interesting finding and may have important repercussions. Lymphocytes, for example, help orchestrate specific adaptive immune responses against invading agents such as pathogenic microorganisms. As sufficient lymphocyte production is crucial for developing holistic immune competence, an imbalance in lymphocyte production induced by TCDD may have pathological consequences. His research further showed that cellular expression of key genes such as BCL11A and IRF8 that are involved in the development of lymphoid and dendritic cells from HSPCs were suppressed by TCDD which may explain the TCDD mediated perturbation of hematopoiesis.

Khan’s research has also been an integral part of the ongoing work of the MSU Superfund Research  Program. One of the goals of the program is to identify molecular responses to environmental contaminants that act as agonists for the AHR in different systems, such as in the context of the immune system. Khan’s research contributes to a better understanding of the adverse effects of TCDD on the developing human immune system. “To my knowledge, this is the first time that the effect of TCDD on gene regulation during human hematopoietic stem and progenitor cell (HSPC) differentiation has been studied at the single cell transcriptomic level,” commented Khan. “Specific signaling pathways and genes that have been found to be altered by TCDD in HSPCs may be useful to understand the mechanisms by which AHR activators exert toxicity and help develop strategies in the future to counteract such phenomena.”

Khan is also interested in testing the functional capabilities of some of the immune cells that develop in the developmental assay. Using different approaches, Khan hopes to test the effect of TCDD on immune cell function as well as delineate the role of different signaling pathways in TCDD mediated alterations in hematopoiesis. Moreover, with the increasing adoption of new approach methodologies to replace animal models, the multilineage model of human hematopoiesis that Khan has identified and characterized could be useful to test the effects of other toxicants on human hematopoiesis.