Antoine, B. | bioRxiv Science

bioRxiv2024

Trajectory analysis of hepatic stellate cell differentiation reveals metabolic regulation of cell commitment and fibrosis

Defining the trajectory of cells during differentiation and disease offers the possibility to understand the mechanisms driving cell fate and identity. However, trajectories of human cells are largely unexplored. By investigating the proteome trajectory of iPSCs differentiation to hepatic stellate cells (dHSCs), we identified RORA as a key transcription factor governing the metabolic reprogramming of HSCs necessary for HSCs commitment, identity, and activation. Using RORA deficient iPSCs and pharmacologic interventions, we showed that RORA is required for mesoderm differentiation and prevents dHSCs activation by reducing the high energetic state of the cells. While RORA knockout mice had enhanced fibrosis, RORA agonists rescued multi- organ fibrosis in in vivo models. RORA expression was consistently found to be negatively correlated with liver fibrosis and HSCs activation markers in patients with liver disease. This study reveals that RORA regulates cell metabolic plasticity, crucial for mesoderm differentiation, pericyte quiescence, and fibrosis, influencing cell commitment and disease mechanisms. SummaryThis study describes the trajectory of induced pluripotent stem cells (iPSCs) differentiation to hepatic stellate cells (dHSCs). We identify RAR-related orphan receptor alpha (RORA) as a transcription factor essential for mesoderm commitment and dHSCs identity and fibrogenic activation by regulating metabolic plasticity.

cell biology↗

bioRxiv2019

Prevalence of chronic chikungunya and associated risks factors in the French West Indies (La Martinique). A prospective cohort study

BackgroundThe chikungunya virus (CHIKV) is a re-emerging alphavirus that can cause chronic rheumatic musculoskeletal disorders, named chronic chikungunya (CHIKC+), which may be long-term incapacitating. A chikungunya outbreak occurred in 2013 in La Martinique. We constituted the first prospective cohort study of CHIKV-infected subjects in the Caribbean to assess the prevalence of CHIKC+ at 12 months and to search for factors present at the acute stage significantly associated with chronicity.\n\nMethodology/Principal findingsA total of 193 patients who tested positive for RT-PCR CHIKV, were submitted to clinical investigations in the acute phase (<21 days), and 3, 6, and 12 months after their inclusion. A total of 167 participants could be classified as either suffering or not from CHIKC+. They were analyzed using logistic regression models. At 12 months, the overall prevalence of CHIKC+ was 52.1% (95%CI: 44.5-59.7). In univariate analysis, age (OR: 1.04; 95% CI: 1.02-1.07; p=0.0003), being male (OR: 0.51; 95%CI: 0.27-0.98; p=0.04), headache (OR: 1.90; 95%CI: 1.02-3.56; p=0.04), vertigo (OR: 2.06; 95%CI: 1.05-4.03; p=0.04), vomiting (OR: 2.51; 95%CI: 1.07-5.87; p = 0.03), urea (OR: 1.33; 95%CI: 1.05-1.70; p=0.02) were associated with CHIKC+. In final multivariate logistic regression models for 167 participants, predictors of CHIKC+ were age (OR 1.06; 95%CI: 1.03-1.08; p<0.0001), male sex (OR: 0.40; 95%CI: 0.19-0.84; p=0.015), vertigo (OR: 2.46; 95%CI: 1.16-5.20; p=0.019), hypotension (OR 4.72; 95% -CI: 1.19-18.79; p=0.028), recoloration time >3 seconds (OR: 3.79; 95%-CI: 1.01-14.25).\n\nConclusionsThis cohort study in La Martinique confirms that CHIKC+ is a frequent complication of acute chikungunya disease. Analysis emphasized the importance of age and female sex for CHIKC occurrence, and pointed out the potential aggravating role of dehydration at the acute phase. Early and adequate hydration could reduce the risk chronic chikungunya disorders.\n\nAuthor SummaryChikungunya is a mosquito-borne virus found in tropical countries that has been re-emerging in the last decade. It has caused major epidemics in recent years, such as in Reunion Island and in Southeast Asia. Nearly 2.5 billion people around the world are at risk of contracting the virus. During the acute phase of the illness, patients experience a flu-like syndrome with fever, headache, myalgia, rash, and severe arthralgia. These symptoms can persist for several months in some patients, and can lead to significant functional disability. During the 2013 epidemic in Martinique, we followed nearly 200 patients who had contracted chikungunya. More than half of the patients had a chronic form of the disease--mainly women over 50 years of age. Our statistical analyses indicate that poor hydration during the acute phase may be a risk factor for developing chronic rheumatism. Therefore, in the context of a chikungunya epidemic, it seems important to encourage patients to drink plenty of fluids as soon as the first symptoms appear.

microbiology↗