Bone marrow haematopoietic stem cells influence liver homeostatic networks and cancer development

Abstract

In fatty liver disease, systemic homeostasis is perturbed. While pre-clinical models are used to understand its pathogenesis, translating this knowledge to patients is difficult. However, by focusing on the most preserved homeostasis systems between species and models, novel disease dimensions can be unearthed. We interrogated core liver gene co-expression networks in a mouse model of liver cancer following dietary challenge. The behaviour of immunometabolic networks in tumours mirrored their counterparts in non-tumour liver. These modules showed temporal changes under the influence of diet duration and aging. A high immune response network was associated with a lower tumour burden in mice and humans. This module in mice was enriched for genes related to haematopoietic cell differentiation. Consistently, the bone marrow haematopoietic stem and progenitor cells response was reflective of the liver immune response. Linking haematopoiesis to hepatic homeostasis uncovers a hitherto unexplored dimension of tissue crosstalk that can inform pathogenesis.

Bile acids mediate liver-bone marrow crosstalk

“…We showed that mere dysregulation in cholesterol homeostasis was not sufficient to incite BM HSPC responses in mice, while suppression of bile acid biosynthesis was . Of note, we have previously shown the protective effects of inhibiting bile acid and cholesterol biosynthesis on reducing liver cancer burden 1 . Interestingly, a recent analysis of patients in the IMBrave 150 clinical trial (immunotherapy in HCC) showed that responders had down-regulation in pathways related to cholesterol homeostasis and bile acid synthesis 13 .…”

“…Fatty liver disease associated with metabolic dysregulation also shares these common risk factors. In a previous study we reported the bone marrow haematopoietic responses in mice that develop fatty liver-related liver cancer while on diets of varying composition 1 . However, that study did not allow us to distinguish whether dietary composition exerts effects on the liver and marrow independent of tumour presence, nor could we deduce if liver tumours per se could regulate this process.…”

“…RNA concentration was measured using Nanodrop spectrophotometer (Thermo Fisher). Gene expression was measured by qPCR or by RNA-seq for tumour xenografts, as we reported recently 1 .…”

“…Thus, investigating liver regulatory mechanisms can provide insights on the impact of environmental factors such as diet on the liver, and through this, the impact on other organs. While the liver's cross-talk with other organ systems has been extensively studied, its communication with bone marrow haematopoietic stem cells remains unexplored particularly in the context of metabolic associated fatty liver disease (MAFLD) and liver cancer 1 . We sought to understand the cross-talk between the liver and bone marrow haematopoietic stem cells for new insights on the development and progression of fatty liver and its associated diseases.…”

“…We considered that understanding the geneenvironment interactions that regulate metabolic health is an essential step to unravelling this complex disease 2 . Recently, we observed an association between hepatic gene co-expression networks and bone marrow haematopoietic stem and progenitor cell (BM HSPC) responses that was triggered by dietary composition in a liver cancer model 1 . In this model, upregulation in hepatic immune responses and downregulation in liver metabolism networks correlated with the extent of upregulation in BM HSPC responses to diet.…”