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Research Team at William & Mary

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Research Interests and Goals

Illuminating, profiling and manipulating perivascular plasticity in microvasculature

Smooth Muscle Cells (SMC) make up the involuntary muscles in our body and cover many hollow organs and the vascular system such as arteries, veins, and lymph vessels. Cardiovascular diseases are the leading cause of death due to heart attacks and strokes. Chronic inflammation developing in the adipose tissue of an overweight or obese body also increase cardiovascular risks.

 

  • My postdoc project focused on adipose tissue microvasculature and the role of SMC- derived cells in the context of diet induced obesity. I performed extensive flow cytometric and scRNA sequencing based investigation of cell types in adipose tissue microvasculature. (You can read more here.)

  • Adipose tissue microvasculature consists of highly heterogenous types of stromovascular cell types including macrophages and vascular cells. Interestingly, some macrophage types were increased in response to obesity, and decreased in response to smooth muscle specific knock out of pluripotency factor Klf4.

  • Interestingly, lymphatic smooth muscle cells were increased upon obesity along with decreases in blood pressure regulating SMC clusters. 

  • Understanding cellular heterogeneity in adipose tissue and how it changes in response to obesity is of significant biomedical impact and could lead to novel therapies for diabetes and obesity related microvascular complications. 

Macrophage
Heterogeneity

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Lymphatic
smooth muscle cells

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Obesity promoting
EndoMT

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Investigating adipose tissue macrophage phenotypes :

 

The first dataset in my paper includes adipose tissue stromovascular cells sorted from epidydimal fat of mice fed either normal diet or obesity diet. This dataset presented a large number of macrophages which displayed remarkable plasticity (8 clusters). 

 

My initial goal is to dive deeper into this group of cells, characterize different macrophage types and compare their abundance in chow vs obesity diet conditions. This project is currently funded by the College of William & Mary with a faculty research grant. I have recruited two undergraduate students: Beryl Jiang senior double majoring in Biology and Computer Science at William & Mary and Yuqi Pang, Statistics senior at UVA to explore this dataset using coding in RStudio. 

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Human blood monocyte derived macrophages

Human blood monocytes can be utilized to differentiate and generate macrophage (hBMDM) in tissue culture. This system is highly physiologically relevant and a valuable platform to test molecular, cellular mechanisms related to macrophage biology. 

 

I aim to use  cultured monocyte derived macrophages to recapitulate the differentiated ATM subsets.

Some questions we can ask is, how does an obesity/regression associated cytokine impact the phagocytic capacity of hMDMs? How can we reprogram a lipid associated macrophage back to a lean adipose tissue macrophage? How does the lipid content impact differentiation of monocytes into macrophage types?

In order to study the differences between lymphatic and vascular smooth muscle and how they relate to metabolism, I propose to obtain Lymphatic smooth muscle cells from Dr David Zawieja. We can compare this cell line to aortic SMC line from Dr. Owens’s lab using bulk RNA sequencing to find main differences in terms of gene expression and response to contractile phenotype related cytokines.

I hypothesize that obesity promoting cellular transitions exist within the adipose tissue microvasculature. This is based on my preliminary data in my scRNAseq dataset which shows a bridge of endothelial to mesenchymal transition state cells (Figure 3 above). Importantly, top differentially expressed genes such as Timp4, Mfge8 in this group of cells were shown to promote obesity. Potentially, we could test whether these transitions are causative or is a unavoidable due to change in microenvironment.

I have used Myh11-Lgals3 dual lineage tracing system for intravital and ex vivo imaging to illuminate SMC plasticity. 

 

In the future, it would be a unique research avenue to create a sequential lineage tracer mouse model using Myh11 and Tnnt1-2 to label lymphatic smooth muscle cells which can be used for making knockouts for metabolic experiments and live imaging.

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Overall, I would like to know how we can preserve the health and well-being of macrophages, endothelial cells and vasculature as the adipose tissue transforms during obesity, to prevent dysregulation of blood pressure and vascular permeability.

Previously mentored students

Kritihika Layagala, undergrad at WM

Lillian Waller, Medical Resident at VCU

Ana Tsiskarishvili, District Manager at Vector Marketing

Sophia Kirmani, UVA graduate.

Interested in joining our research group? That is awesome!! Just a kind reminder that we do computational biology and data mining at this point. GB does not have a wet lab. William & Mary Biology department has an outstanding Master's degree program that you can apply.

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