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Abstract To investigate the pathogenesis of a congenital form of hepatic fibrosis, human hepatic organoids were engineered to express the most common causative mutation for Autosomal Recessive Polycystic Kidney Disease (ARPKD). Here we show that these hepatic organoids develop the key features of ARPKD liver pathology (abnormal bile ducts and fibrosis) in only 21 days. The ARPKD mutation increases collagen abundance and thick collagen fiber production in hepatic organoids, which mirrors ARPKD liver tissue pathology. Transcriptomic and other analyses indicate that the ARPKD mutation generates cholangiocytes with increased TGFβ pathway activation, which are actively involved stimulating myofibroblasts to form collagen fibers. There is also an expansion of collagen-producing myofibroblasts with markedly increased PDGFRB protein expression and an activated STAT3 signaling pathway. Moreover, the transcriptome of ARPKD organoid myofibroblasts resemble those present in commonly occurring forms of liver fibrosis. PDGFRB pathway involvement was confirmed by the anti-fibrotic effect observed when ARPKD organoids were treated with PDGFRB inhibitors. Besides providing insight into the pathogenesis of congenital (and possibly acquired) forms of liver fibrosis, ARPKD organoids could also be used to test the anti-fibrotic efficacy of potential anti-fibrotic therapies. 

Mendel's law of segregation explains why genetic variation can be maintained over time. In diploid organisms, an offspring receives one allele from each parent, not just half of the blended genetic material of the parents. Which of the two alleles is received is purely random. This stochastic process generates genetic variation among members of the same family, called Mendelian segregation variance or within‐family variance. In statistics, the genetic value of a quantitative trait for an offspring follows a mixture distribution consisting of the four alleles of the two parents, guided by a Mendelian variable from each parent. The mixture model allows us to partition the total genetic variance into between‐family and within‐family variances. In the absence of inbreeding, the genetic variance splits half to the between‐family variance and half to the within‐family variance. With inbreeding, however, the between‐family variance is increased at the cost of the within‐family variance, leading to a net increase of the total genetic variance. This study defines multiple Mendelian variables and develops a mixture model of quantitative genetics. The phenomenon that allelic variance is maintained over time is guided by “the law of conservation of allelic variance” in biology, which is comparable to “the law of conservation of mass” in physics.