Single-Cell and Spatial Genomics of Diabetic-induced Tissue Remodeling In Human Myocardium

Diabetic cardiomyopathy (DCM) is supposed to result in cardiac dysfunction in patients with diabetes, marked by cardiac remodeling, fibrosis, and inflammation. However, the underlying molecular and cellular processes remain unclear yet. The project aims to elucidate these mechanisms by leveraging cutting-edge single-nuclei RNA sequencing (snRNA seq) and spatial transcriptomics to map the genetic and molecular landscape of diabetic myocardium in humans. Recent advances in single-cell genomics offer insights into disease-driving cellular changes, but spatial transcriptomics provides additional context by retaining the tissue's spatial organization. This is crucial for studying cellular interactions, which often require the surrounding cell compound to promote key pathological processes like fibrosis and hyperinflammation. Previous studies have focused mainly on preclinical in vitro and in vivo models. However, in the context of the project human myocardial tissue samples have been stratified into distinct cohorts according to their underlying clinical diagnosis to understand the pathology on molecular levels.

We included the diseased hearts of transplanted patients with and without diabetes mellitus typ 2. The patients were matched according to age, gender and disease. Diabetes was confirmed by analysing preoperative constant fastening blood glucose over 125 mg/dl or continuous antidiabetic medication; excluding other types or causes of diabetes. The average age of the patients is 57 years with average BMI of 27±1 kg/m2. The entire patient cohort is subclustered into four different subgroups: Diabetic patients with ischemic cardiomyopathy and diabetic patients with dilated cardiomyopathy as well as non-diabetic patients with ischemic cardiomyopathy and non-diabetic patients with dilated cardiomyopathy  Each of these subgroup contains 19-20 patients, consisting of 9-10 male and 9-10 female individuals, adding up to 77 diseased patients. 20 rejected donor hearts were used as controls. Thereby, the entire cohort consist of nearly 100 different human individuals.

By integrating spatial genomic data, we could map cell-specific regulatory mechanisms within myocardial tissue, define cellular subclusters, and uncover interaction networks driving the disease progression. The project’s multiomic approach helps to identify cell-specific pathways relevant for diabetic remodeling. Thereby, it is possible to identify potential molecular drivers of the disease and evaluate these markers as therapeutic targets in additional in vitro validation systems.

This work provides a high-resolution molecular data set that can elucidate the molecular processes of the myocardial dysfunction in diabetic patients, accelerate the investigation of potential therapeutic targets and therefore, address a growing clinical need for precision medicine in the treatment of DCM.