We are actively investigating pediatric sepsis-associated myocardial dysfunction (SAMD), focusing on the response of human induced pluripotent stem cell (iPSC)-derived cardiomyocytes to serum factors from children with septic shock, as well as patterns of susceptibility to SAMD using patient-specific iPSC-cardiomyocytes. In collaboration with the Atreya Laboratory, we are also developing a biorepository of patient-specific iPSCs from children with septic shock to unravel mechanisms of organ dysfunction.

iPSC-Cardiomyocyte Response to Septic Serum

iPSC-derived cardiomyocytes are a renewable platform to study the human cardiomyocyte response to septic serum and specific circulating myocardial depressant factors. We use small molecules to direct iPSCs to differentiate into cardiomyocytes in our laboratory, which spontaneously beat. We have demonstrated that serum from children with SAMD reliably depresses the contractility of iPSC-cardiomyocytes, compared to serum from children with sepsis but no SAMD. To contextualize and better understand the mechanisms driving these changes in contractility, we measure a variety of readouts, including mitochondrial function and changes in gene expression. We have also begun to examine the role of specific cytokines and serum factors in SAMD through modulation of signaling pathways in iPSC-cardiomyocytes.

Host Genetic Background in SAMD

SAMD occurs in children of all ages and co-morbidities, and it remains unclear why some children develop SAMD with septic shock while others do not. Patient-specific iPSCs from children with septic shock afford an opportunity to investigate the impact of host genetic background on SAMD by exposing iPSC-cardiomyocytes from children with and without SAMD to serum from children with and without SAMD. Beyond changes in cardiomyocyte function, we are investigating patterns of gene expression that might define novel pathways involved in pediatric SAMD.

Host Genetic Background in SAMD Figure. 

Schematic depicting investigation into host cardiomyocyte contribution to SAMD.

Patient-Specific iPSC Sepsis Biorepository

Our laboratory is interested in disentangling cell- and organ-specific pathophysiology in septic shock and multiple organ dysfunction syndrome. Biologic heterogeneity within and between patients complicates the development of new therapeutic approaches for children with septic shock, and there is a critical need for a pediatric sepsis biorepository to facilitate mechanistic research to provide new insights and to support precision medicine in pediatric sepsis. In collaboration with the Atreya Laboratory, we are building upon Dr. Hector Wong’s biorepository of serum from children with septic shock to create a sepsis biorepository of patient-specific iPSCs annotated with clinical organ dysfunction phenotypes. This biorepository will enable both the development of clinically relevant cellular and organoid models of sepsis injury and organ dysfunction and the study of host contributions to organ injury in pediatric septic shock.

Grant Support:

Mechanisms of cardiomyocyte dysfunction in pediatric septic shock.

  • PI: Andrew Lautz. Project Number: NIH 1K08GM148957-01.

Establishment of a multi-center biobank of patient-specific pluripotent stem cells for pediatric sepsis research.

  • MPI: Mihir Atreya and Andrew Lautz. Project Number: NIH 1R21GM150093-01.

Novel human modeling of pediatric sepsis-associated myocardial dysfunction.

  • PI: Andrew Lautz. Project Number: NIH 2L40GM134527-02.