Microbiota from Obese Mice Regulate Hematopoietic Stem Cell Differentiation by Altering the Bone Niche

Abstract

The effect of metabolic stress on the bone marrow microenvironment is poorly defined. We show that high-fat diet (HFD) decreased long-term Lin(-)Sca-1(+)c-Kit(+) (LSK) stem cells and shifted lymphoid to myeloid cell differentiation. Bone marrow niche function was impaired after HFD as shown by poor reconstitution of hematopoietic stem cells. HFD led to robust activation of PPARγ2, which impaired osteoblastogenesis while enhancing bone marrow adipogenesis. At the same time, expression of genes such as Jag-1, SDF-1, and IL-7 forming the bone marrow niche was highly suppressed after HFD. Moreover, structural changes of microbiota were associated to HFD-induced bone marrow changes. Antibiotic treatment partially rescued HFD-mediated effects on the bone marrow niche, while transplantation of stools from HFD mice could transfer the effect to normal mice. These findings show that metabolic stress affects the bone marrow niche by alterations of gut microbiota and osteoblast-adipocyte homeostasis.

The initiation of metabolic inflammation in childhood obesity

“…In addition, obesity may also influence HSC function indirectly by modifying the bone marrow niche populated with specialized adipocytes (120). The obese gut microbiome has been implicated in stimulating myelopoiesis via modification of the bone marrow niche (121).…”

Maternal modifiers of the infant gut microbiota: metabolic consequences

“…Dietary changes can have major effects on microbial composition and release of LPS that provokes inflammation, insulin resistance, and may even program bone marrow-derived stem cells (Giusti et al 2017). The significant increase in common myeloid progenitor cells derived from the bone marrow in diet-induced obese mice is thought to be the result of an altered microbiota composition (Luo et al 2015). Indeed, recent evidence has emerged to indicate that innate immune memory can be transferred via hematopoietic stem and progenitor cells that alter the function of their differentiated progeny (Ng et al 2013), depending upon the composition of the microbiota (Burgess et al 2014).…”

Hematopoietic Stem Cell Regulation by Type I and II Interferons in the Pathogenesis of Acquired Aplastic Anemia

“…MSC differentiation into either adipogenic or osteogenic progenitors is controlled by cell intrinsic and extrinsic mechanisms (123, 124). Systemic inflammation, as induced by high-fat diet, was recently linked to PPARγ activation in MSCs and resultant adipogenesis, concomitant with a reduction in HSPC support by the microenvironment (125). Severe AA, therefore, could erode BM microenvironmental function and HSC niches by a similar mechanism.…”