Biology subjects

Friesen, M.

Publications and source records attributed to Friesen, M..

4 recordsLinked to original sources

bioRxiv2025

Modeling physiological insulin sensitivity and pre-diabetic insulin resistance in multiple hPSC-derived cell types

Recently, we demonstrated the development of a human pluripotent stem cell (hPSC)-derived adipocyte (fat cell) model with physiological insulin signaling. For the first time, a human in vitro adipocyte cell model has an insulin response similar to in vivo human adipocytes. We next leveraged this protocol to study the early stages of insulin resistance preceding Type 2 Diabetes, by exposing these cells to diabetic patient levels of hyperinsulinemia. This resulted in mild insulin resistance on all of the aforementioned phenotypes, reminiscent of early T2D development in humans. This is a powerful model to study the mechanisms of T2D development and the underlying molecular pathology. However, while adipocytes are an important metabolic cell type, insulin resistance and T2D are a whole-body affliction, involving many other cell types. To broaden the impact of our work and increase the excitement of the field for the study of insulin signaling and resistance, we expanded our protocol to a panel of 8 other hPSC-derived cell types. We demonstrate physiologically relevant insulin response for each cell type, and we highlight that our insulin-resistance inducing conditions blunt the insulin response in every cell type. Additionally, we validate that key cell identity markers are not lost during this adaptation. By adapting a simple, defined protocol to a wide panel of human in vitro cell types, we can now investigate the cell-autonomous origins of insulin resistance under physiologically relevant conditions.

cell biology↗

bioRxiv2025

Healthy adipocytes provide a protective environment by limiting viral infection through cell-cell communication

Adipocytes, long regarded primarily as energy storage cells, are increasingly recognized as active players in immune regulation. In metabolic disorders such as obesity and diabetes--conditions characterized by adipocyte dysfunction--patients often exhibit worsened outcomes following viral infections. However, the role of healthy adipocytes in modulating antiviral immunity remains poorly understood. Here, we demonstrate that healthy adipocytes secrete factors that confer antiviral protection to neighboring cells. We developed a fully human pluripotent stem cell (hPSC)-derived system including adipocytes, immune, and vascular cells to evaluate the antiviral capacity and infectivity of various cell types. Our cell system has the advantage of being of human origin, as opposed to animal models. Through our technological development, we have removed cell culture medium as a variable by adapting all cell types to a single base medium. We found that only adipocytes could induce an antiviral state in adjacent mural and immune cells. This unique immunomodulatory capacity is mediated, at least in part, by the STING-dependent secretion of low levels of interferon-alpha (IFN-) from healthy adipocytes. Notably, pharmacological induction of metabolic dysfunction in adipocytes diminished their antiviral activity, revealing a previously unrecognized link between metabolic health and antiviral defense. These findings identify a novel role for adipocytes in orchestrating local antiviral responses and provide new insight into how metabolic dysfunction may compromise host defense during viral infections.

cell biology↗

bioRxiv2023

SARS-CoV-2 infection of human pluripotent stem cell-derived vascular cells reveals smooth muscle cells as key mediators of vascular pathology during infection

Although respiratory symptoms are the most prevalent disease manifestation of infection by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), nearly 20% of hospitalized patients are at risk for thromboembolic events. This prothrombotic state is considered a key factor in the increased risk of stroke, which is observed clinically during both acute infection and long after symptoms clear. Here we develop a model of SARS-CoV-2 infection using human-induced pluripotent stem cell-derived endothelial cells (ECs), pericytes (PCs), and smooth muscle cells (SMCs) to recapitulate the vascular pathology associated with SARS-CoV-2 exposure. Our results demonstrate that perivascular cells, particularly SMCs, are a susceptible vascular target for SARS-CoV-2 infection. Utilizing RNA sequencing, we characterize the transcriptomic changes accompanying SARS-CoV-2 infection of SMCs, PCs, and ECs. We observe that infected SMCs shift to a pro-inflammatory state and increase the expression of key mediators of the coagulation cascade. Further, we show human ECs exposed to the secretome of infected SMCs produce hemostatic factors that contribute to vascular dysfunction, despite not being susceptible to direct infection. The findings here recapitulate observations from patient sera in human COVID-19 patients and provide mechanistic insight into the unique vascular implications of SARS-CoV-2 infection at a cellular level.

microbiology↗

bioRxiv2022

Development of a physiological insulin resistance model in human stem cell-derived adipocytes

Adipocytes are key regulatory cells of human metabolism, and their dysfunction in insulin signaling is central to metabolic diseases such as type II diabetes mellitus (T2D). However, the progression of insulin resistance that leads to T2D is still poorly understood. This limited understanding is due, in part, to the dearth of suitable models of insulin signaling in human adipocytes. Traditionally, in vitro adipocyte models fail to recapitulate in vivo insulin signaling, possibly due to exposure to supraphysiological nutrient and hormone conditions. Here, we have developed a sensitization protocol for human pluripotent stem cell-derived adipocytes that uses physiologically relevant nutrient conditions to produce a potent signaling response comparable to in vivo adipocytes. After systematically optimizing conditions, this protocol allows for robust insulin-stimulated glucose uptake and transcriptional insulin response. Furthermore, exposure of these sensitized adipocytes to physiologically relevant hyperinsulinemic conditions dampens insulin-stimulated glucose uptake and dysregulates transcription of insulin-responsive genes. Overall, this sensitization methodology provides a novel platform for the mechanistic study of insulin signaling and resistance using human pluripotent stem cell-derived adipocytes. TeaserA new protocol to generate hPSC-adipocytes that respond to physiological insulin levels and can model diabetes.

cell biology↗