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Unleashing the potential of human induced pluripotent stem cells (hiPSCs) to better understand the biology of critically ill children with sepsis.

Mihir R. Atreya, MD, MPH
Andrew J. Lautz, MD
Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center.

Sepsis is an abnormal host response to an infection and is a leading killer of children under 5-years of age across the world. Those lucky to survive, are at increased risk of future infections, dependence on medical technologies, and life-long risk of cardiovascular disease. In the U.S alone, care associated with pediatric sepsis exceeds $7 billion each year. However, despite this burden of disease, care for children with sepsis, who are admitted to the pediatric intensive care unit (PICU), remains limited to early antibiotics and intensive organ support through the use of ventilators and dialysis machines. A major obstacle is that patients with sepsis may present with different sources of infection, with different degrees of immune response to the infection, and develop varying degrees of organ failure. An understanding of mechanisms at the cellular and organ-system level, while accounting for these between-patient differences, is therefore necessary to advance sepsis research and ultimately care of patients at the bedside. Currently, this is greatly limited by the amount and type of biological specimens that can be collected from very sick children.

Over the previous decade, researchers at Cincinnati Children’s have pioneered scientific advances in using small amounts of blood or skin cells to turn them into induced pluripotent stem cells (iPSCs) to better understand several complex diseases. Using very little amounts of blood, these human iPSCs can be converted into any cell type of interest, including cells that are usually inaccessible or very rare, to study underlying molecular mechanisms. Moreover, different cell types can be used in combination to develop complex structures called ‘organoids’ in petri dishes. As such, both human iPSCs and organoids are transformative platforms to study patient biology as they capture human genetic diversity and more closely mimic patient biology in comparison with traditional mouse models. Most importantly, iPSCs are a renewable resources of patient specimens, which is a critical consideration for pediatric patients. These research efforts have been bolstered by the investment in state-of-the-art institutional facilities including the Pluripotent Stem Cell Facility (PSCF) and Center for STem cell and Organoid Medicine (CuSTOM).

An investigator team lead by faculty in our division has recently secured federal funding through a phased innovation award by the National Institute of General Medical Sciences (NIGMS), a key institute under the National Institutes of Health (NIH), to test whether human iPSCs derived from critically ill children with sepsis can be used to develop more relevant and reproducible disease models for future studies. The key goals of the project are to (1) validate new approaches to blood specimen collection, (2) to generate patient-specific iPSCs, and (2) to use high throughput sequencing approaches to determine how closely iPSCs can recapitulate patient biology at the genetic level. This collaborative proposal builds on our long-standing multi-center pediatric sepsis biorepository led by the late Dr. Hector Wong and provides us the opportunity to transform it to meet the needs of the next generation of scientific inquiry. Ultimately, we hope that our patient-specific human iPSC biorepository will help unravel patient biology through advanced organoid models, accelerate mechanistic research, and lead to the discovery of precision therapeutics that can meaningfully improve outcomes of critically ill children with sepsis.

Unleashing The Potential Of Human Induced Pluripotent Stem Cells (hiPSCs) To Better Understand The Biology Of Critically Ill Children With Sepsis.
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