CARDIOLOGY
Circulating Cast continued
The environmental connection
Aside from the cardiovascular system, the lateral plate mesoderm also gives rise to mesothelial cells, which provide a sort of protective shrink wrap for organs and produce mucous to lubricate them. Dr. Mosimann’ s team isolated the first genetic program that sets them apart from other cells in the LPM. It’ s the same program they use to repair themselves, after, say, a surgical incision.
And in the case of mesothelioma, a type of lung cancer triggered by asbestos fibers, Dr. Mosimann’ s team found that it’ s that same genetic program that goes awry.
“ It’ s just an example of a way we can connect developmental biology to environmental factors, in this case asbestos exposure,” says Dr. Mosimann.“ It’ s a bigger story than just glow-in-the-dark fish.”
have problems with their joints and kidneys too.’ And our clinician colleages somewhere down the road can make those connections and make a care plan that improves that kid’ s quality of life.”
FREE-FLOATING PREDICTORS
As clinicians, one of the most vexing problems Drs. Miyamoto and Nakano encounter in their patients is the unpredictable heterogeneity of outcomes. Some kids with, say, single ventricle heart disease do really well. With the help of three well-established operations that reconfigure their circulation, they can live long, relatively healthy lives.
Others’ hearts’ fail. That’ s a growing public health problem, particularly as better treatments lead to longer survival for kids with serious heart anomalies( 4). A transplant might last fifteen years. For a 2-year-old, that’ s a lot of heart transplants down the road.
A much better solution would be to preserve the existing heart, but that’ s a complicated problem to figure out. In the adult world, for example, many studies are done with biopsies. They’ re relatively routine. For kids, whose hearts are much smaller, they’ re intolerably risky. Dr. Miyamoto’ s researchers get around that working with explanted tissues. But they’ re also, increasingly, looking at the blood.
“ If we could predict who would do poorly that could help inform treatment,” Dr. Miyamoto says.“ We’ re trying to find cells and other
In color: the beginnings of the lateral plate mesoderm, developmental precursor to the heart and circulatory system. Photos by Hannah Moran
biomarkers that can do that, but we need to be able to get them from a blood draw.”
As she transitions from Dr. Miyamoto’ s lab to independent research, Dr. Nakano is currently focused on those circulating biomarkers. In fact, last year she identified a set of circulating microRNAs that predicted survival or either transplant or death by one year of age.
She’ s now investigating the potential role of the immune system through rigorous classification of the peripheral blood mononuclear cells, or PBMCs, in the blood of single ventricle patients on their way to surgery. Working with the Human Immune Monitoring Shared Resource, or HIMSR Core, a collaborative immunology lab on the Anschutz Campus, Dr. Nakano is working to define the types of immune cells in circulation, their activation status and what kind of cytokines they may produce.
“ In order to really figure out if a cell type works as a marker, if it’ s a good surrogate for what’ s happening in the heart,” she says,“ you need to know exactly what you’ re working with.”
And if that doesn’ t work out, well, there are plenty of other fish in the sea. •
Cover photo by Hannah Moran( left image) and Christian Mosimann, PhD( right image).
1. Nakano SJ, Walker JS, Walker LA, Li X, Du Y, Miyamoto SD, Sucharov CC, Garcia AM, Mitchell MB, Ambardekar AV, Stauffer BL. Increased myocyte calcium sensitivity in end-stage pediatric dilated cardiomyopathy. Am J Physiol Heart Circ Physiol. 2019 Dec 1; 317( 6): H1221-H1230.
2. Prummel KD, Nieuwenhuize S, Mosimann C. The lateral plate mesoderm. Development. 2020 Jun 19; 147( 12): dev175059.
3. Prummel, K. D., Hess, C., Nieuwenhuize, S. et al. A conserved regulatory program initiates lateral plate mesoderm emergence across chordates. Nat Commun 10, 3857( 2019).
4. Nakano SJ, Miyamoto SD, Price JF, Rossano JW, Cabrera AG. Pediatric Heart Failure: An Evolving Public Health Concern. J Pediatr. 2020 Mar; 218:217-221.
10 | CHILDREN’ S HOSPITAL COLORADO