Role of hematopoietic reprogramming in myocardial damage after allogeneic transplantation

• Applicant: Professor Dr. Thimoteus Speer, Ph.D.
• Subject Area: Nephrology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 566291583

Allogeneic organ transplantation represents the only treatment for terminal heart, lung, liver, or kidney failure. However, rejection episodes, and chronic graft failure limit the long-term outcome. Transplant recipients face a higher cardiovascular (CV) risks compared to the general population. The risk of coronary artery disease (CAD) is 2.7 times higher than in the general population, and CV deaths account for 25–50% of post-kidney transplant mortality. Myocardial infarction (MI) represents a frequent complication, with kidney transplant recipients facing a 1.5-fold increased risk. Inflammation is a known risk factor, but specific therapies to reduce CV risk after transplantation are lacking. This project aims to investigate how allogeneic transplantation affects the hematopoietic system and reprograms the innate immune system, leading to secondary myocardial damage. The goal is to identify novel therapeutic targets to reduce CV complications. The project is divided into four work packages. The first work package focuses on characterizing the innate immune response to transplantation by analyzing the composition of bone marrow cells using flow cytometry and single-cell technologies. It will also assess how bone marrow and splenic monocytes respond to inflammatory signals and examine the spatial organization of the hematopoietic system. The second work package investigates how allogeneic transplantation alters the hematopoietic system and increases the risk of myocardial damage. The third work package assesses the clinical relevance of these findings by examining peripheral blood mononuclear cells (PBMCs) from kidney transplant patients, both with stable outcomes and those experiencing acute rejection. These cells will be examined for their effects on myocardial injury in cardiac organoids and NOD-SCID mice subjected to myocardial infarction. The fourth work package explores the underlying mechanisms of hematopoietic reprogramming. It focuses on how key metabolites such as citrate, lactate, and malate influence immune cell differentiation. Specifically, it will study how extracellular lactate shuttling affects long-term hematopoietic stem cell differentiation using bone marrow organoid models and mice lacking specific lactate transporters. We hypothesize that allogeneic transplantation triggers an inflammatory response that alters alpha-keto acid levels in the bone marrow. These metabolic changes, particularly the accumulation of lactate, induce epigenetic modifications that shift hematopoiesis toward myelopoiesis, leading to an exaggerated inflammatory response. This increases the susceptibility to secondary myocardial infarction and worsens patient outcomes. By uncovering these mechanisms, the project aims to improve understanding of myocardial injury after transplantation and explore lactate modulation as a potential therapy to reduce cardiovascular risks in transplant recipients.

• DFG Programme: Research Grants