Understanding Hypoxia Through a New Lens: Generating Cardioids
By: Katherine Krieger (Trinity '24)
March 2022
Organoids: What Are They?
Organoids are 3D multicellular tissue structures derived from stem cells in vitro, functioning as their corresponding in vivo organs. Development of organoid tissue structures mimic natural development of body-specific organs, utilizing either pluripotent or adult stem cells. These 3D models mimic key aspects of the complexity of the organ selected for, including the expression of certain cell types and cavities on a micro scale. To date, scientists have reported organoid developments that mimic the brain, retina, lung, intestine, kidney, liver, and heart, labeled “cardiods.”
Numerous clinical and molecular applications are made possible by organoids. An important clinical revolution utilizing organoids is the heightened ability for personalized treatment, including the capacity to test personal drug response and potential development of surgical grafts constructed from own bodily tissue. Regarding basic research, applications of organoid studies include exploring organ-specific developmental processes, responses to external stimuli, mechanisms of homeostasis, and comparisons across species. This molecular potential of organoid study is the main tool for our experiment.
Our Goal
The heart is a key tissue that experiences detrimental effects during tissue hypoxia. In humans, reperfusion injury follows ischemia events that occur during myocardial infarction, stroke, embolism, and other peripheral vascular diseases. These events activate cellular pathways that upregulate pro-inflammatory signaling and promote oxidant generation. Recruitment of inflammatory cells to the vascular wall of the heart further exacerbates oxidant production and ultimately results in cell death, tissue injury, and organ dysfunction. Known in humans, these inducible genes are controlled by transcriptional coactivatiors HIF-1α and HIF-2α.
Diving mammals tolerate repetitive episodes of peripheral ischemia as a part of the cardiovascular adjustments supporting long duration dives. Such adjustments allow marine mammals to optimize the use of body oxygen stores while diving, but can result in selectively reduced perfusion to peripheral tissues. Remarkably, diving mammals show no apparent detrimental effects associated with these ischemia events.
Our research goal is to culture both human and marine mammal cardioids in order to uncover differing molecular pathways that occur during hypoxia events. To do this, we must first create marine mammal stem cells, which can be differentiated from fibroblast cultures. Then, marine mammal and human stem cells are cultured in specific conditions to develop cardioids. Once we have reached this point, we can expose each cardioid culture to hypoxia conditions and study the molecular mechanisms underlying each species’ stress responses.
