A significant portion of the United States population, exceeding 100 million individuals, contends with metabolic dysfunction-associated steatotic liver disease (MASLD). This condition is marked by an undue accumulation of lipids within the hepatic tissue, which can escalate into more serious liver ailments characterized by inflammatory processes and fibrotic changes.
In an endeavor to forge novel therapeutic interventions for these hepatic pathologies, a team of engineers at MIT has conceptualized and engineered an advanced tissue model. This innovative design more faithfully emulates the intricate vascular and cellular architecture of the liver, encompassing its intricate blood vessel network and resident immune cells.
The investigational findings, disseminated today in the esteemed journal Nature Communications, indicate that this meticulously crafted model exhibits a remarkable capacity to accurately simulate the inflammatory responses and metabolic derangements observed during the nascent phases of liver disease. Such a sophisticated apparatus holds considerable promise for advancing the identification and validation of prospective pharmaceutical agents designed to combat these specific conditions.
This latest scientific contribution forms a component of a broader, ongoing initiative by the research cadre. Their overarching objective involves leveraging these sophisticated tissue constructs, also referred to as microphysiological systems, to delve deeper into the complexities of human liver biology. This area of study has historically presented challenges due to the limitations of animal models, such as mice, in fully recapitulating human physiological responses.
In a parallel recent publication, the researchers utilized an earlier iteration of their hepatic tissue modeling system to scrutinize the liver’s reaction to resmetirom. This particular pharmacological agent is employed in the management of an advanced liver condition known as metabolic dysfunction-associated steatohepatitis (MASH). However, its efficacy is presently confined to approximately 30 percent of patients. The research team’s investigation revealed that the drug can precipitate an inflammatory cascade within the liver tissue, a finding that may shed light on the variable patient responses observed.
“While existing tissue models offer robust preclinical assessments of drug-induced hepatotoxicity for certain therapeutic compounds, there remains a critical imperative to enhance our modeling of disease states,” stated Linda Griffith, the School of Engineering Professor of Teaching Innovation at MIT, a distinguished figure in biological and mechanical engineering, and the senior author of both studies. “Our current focus is on pinpointing drug targets, validating their potential, and discerning whether a specific medication might prove more beneficial in the early or later stages of disease progression.”
Dominick Hellen, a former MIT postdoc, spearheaded the research detailed in the resmetirom paper, which debuted on January 14th in Communications Biology. Erin Tevonian, PhD ’25, and Ellen Kan, a PhD candidate, both affiliated with the Department of Biological Engineering, are credited as the lead authors for the current Nature Communications paper, which elaborates on the novel microphysiological system.
Modeling drug response
Within the scope of the Communications Biology publication, Griffith’s laboratory employed a microfluidic device, initially conceptualized in the 1990s and termed the LiverChip. This platform provides a straightforward substrate for cultivating three-dimensional liver tissue models using hepatocytes, the liver’s principal cellular components.
This LiverChip is extensively utilized by the pharmaceutical industry to ascertain whether novel drug candidates elicit deleterious effects on the liver. This evaluation is a pivotal juncture in drug development, primarily because the liver serves as the primary metabolic organ for the majority of pharmaceutical compounds.
For the present investigation, Griffith and her students undertook modifications to the LiverChip to facilitate its application in the study of MASLD.
Individuals afflicted with MASLD, characterized by hepatic fat infiltration, are susceptible to the eventual development of MASH. MASH represents a more severe manifestation where the formation of scar tissue, known as fibrosis, compromises liver function. Presently, resmetirom and the GLP-1 agonist semaglutide stand as the sole FDA-approved pharmaceutical interventions for MASH. Consequently, the pursuit of novel therapeutic agents is deemed a paramount objective, as underscored by Griffith.
“The challenge of liver disease is not one that can be definitively overcome with a single drug or a narrow class of medications,” Griffith emphasized. “Over time, patient populations may emerge who cannot tolerate these treatments, or they may prove to be less effective for a broader spectrum of individuals.”
To construct a representative model of MASLD, the researchers subjected the hepatic tissue to elevated concentrations of insulin, in conjunction with substantial quantities of glucose and fatty acids. This regimen induced adipogenesis within the tissue and fostered the development of insulin resistance, a hallmark frequently observed in MASLD patients and a precursor to type 2 diabetes.
Following the successful establishment of this disease model, the researchers administered resmetirom to the tissue. This drug operates by simulating the actions of thyroid hormone, thereby promoting lipid catabolism.
In a surprising revelation, the research team observed that this therapeutic intervention also triggered an escalation in immune signaling and the expression of inflammatory markers.
“Given that resmetirom’s primary objective is to mitigate hepatic fibrosis in MASH, we found this outcome to be quite counterintuitive,” remarked Hellen. “Our hypothesis is that this finding may contribute to a clearer understanding, for both clinicians and scientists, of why only a subset of patients exhibits a favorable response to this thyromimetic drug. Nevertheless, further experimental investigations are requisite to fully elucidate the underlying mechanistic pathways.”
A more realistic liver model
In their Nature Communications paper, the researchers unveiled a novel chip design that enables a more precise replication of the human liver’s intricate architectural composition. The pivotal advancement lay in the successful development of a methodology to stimulate the in-growth of blood vessels into the engineered tissue. These nascent vessels are instrumental in supplying vital nutrients and also facilitate the transmigration of immune cells throughout the tissue construct.
“The creation of more sophisticated liver models that integrate features of vascularity and immune cell trafficking, while maintaining viability over extended culture periods, is of immense value,” Griffith commented. “The true breakthrough here was demonstrating our ability to establish an intimate microvascular network within the liver tissue and to achieve the circulation of immune cells. This capability allowed us to delineate the differential interactions of immune cells with hepatic cells under conditions simulating type 2 diabetes versus a healthy physiological state.”
As the liver tissue underwent maturation, the researchers artificially induced insulin resistance by exposing it to augmented levels of insulin, glucose, and fatty acids.
Concurrent with the progression of this disease state, the researchers documented alterations in the capacity of hepatocytes to internalize insulin and metabolize glucose. Furthermore, they observed a constriction and increased permeability of the vasculature, mirroring microvascular complications commonly associated with diabetic patients. Their findings also indicated that insulin resistance correlates with an elevation in inflammatory markers that serve to recruit monocytes into the tissue. Monocytes represent the progenitor cells of macrophages, a class of immune cells crucial for tissue repair during inflammatory processes, and are frequently identified in the livers of individuals in the early stages of liver disease.
“This research unequivocally demonstrates our ability to model the immunologic facets of diseases like MASLD, utilizing exclusively human cellular components,” Griffith affirmed.
Financial backing for this research was provided by the National Institutes of Health, the National Science Foundation Graduate Research Fellowship program, NovoNordisk, the Massachusetts Life Sciences Center, and the Siebel Scholars Foundation.
