Microbiota regulates bone marrow mesenchymal stem cell lineage differentiation and immunomodulation

Abstract

Health is dependent on the homeostasis of both inner and external microenvironments. The microbiota as the external microenvironment plays a critical role in regulation of several organ systems in mammals. However, it is unclear whether the microbiota regulates homeostasis of the skeletal system and bone marrow mesenchymal stem cells (BMMSCs). Here, using a well-established germ-free (GF) mouse model, we show that the microbiota significantly alters the stemness of BMMSCs in comparison to specific-pathogen-free (SPF)-derived BMMSCs. Colonization of GF mice with SPF microbiota (conventionalized (ConvD)) normalizes the proliferation and differentiation abilities of BMMSCs. On the other hand, normal microbiota is required to maintain immunomodulatory properties of BMMSCs through induction of activated T-cell apoptosis and cytokine secretion. GF-derived BMMSCs lose the capacity to ameliorate disease phenotypes in dextran sulfate sodium-induced experimental colitis mice. Mechanistically, single-cell RNA-sequencing analysis shows that ConvD BMMSCs have a similar gene expression pattern to SPF-derived BMMSCs, which have a distinct gene distribution from GF-derived BMMSCs.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0670-7) contains supplementary material, which is available to authorized users.

Specific Commensal Bacterium Critically Regulates Gut Microbiota Osteoimmunomodulatory Actions During Normal Postpubertal Skeletal Growth and Maturation

“…Considering reports in C57BL/6 SPF versus GF mice have shown that the normal gut microbiota can blunt bone modeling/remodeling and suppress osteoblastogenesis, alterations in osteoblastogenesis were evaluated in EF versus MPF mice (Fig. ).…”

Reconstitution of the host holobiont in germ-free rats acutely increases bone growth and affects marrow cellular content

“…For example, GH and IGF-1 axes, which are probably upregulated in our model, in general have a negative effect on marrow adiposity making them less likely to be involved in observed BMAT expansion (Menagh et al, 2010). Although very little is known about the effect of microbiota and SCFA on marrow adipocytes, there are some indications of direct gut-BMAT communication with one report showing spontaneous adipocytic differentiation of mesenchymal cells derived from pig bone marrow in response to butyrate treatment (Tugnoli et al, 2019) and the other showing increased adipogenesis and decreased osteogenesis in germ-free-conventionalized mice (Xiao et al, 2017). However, besides determining axes stimulating BMAT expansion in GFC rats, it is even more important to characterize the function of these newly formed adipocytes.…”

Mesenchymal stem cell–gut microbiota interaction in the repair of inflammatory bowel disease: an enhanced therapeutic effect

“…Invariably, MSC‐therapy does not only aim at restoring the desired host immune response but also correct the altered gut microbiota whilst FMT restores gut dysbiosis resulting in dampened inflammation. These functions interlace and may even yield higher therapeutic influence when co‐administered since the few existing investigations report the close communication and enhanced functionality of each other in their interactions [47, 67–70, 71].…”

“…Gastrointestinal bacteria are capable of inducing immune‐regulatory mediator secretions, cytokine gene transcription and surface protein expressions in MSCs [70]. While Xiao et al revealed that, microbiota alters the differentiation potentials and improves the immunomodulation ability of bone marrow MSCs [67], another research also indicated that a restored diversity of gut microbiome, reinstates bone marrow‐derived MSCs from premature age‐associated deterioration and loss of cell power of growth and division (senescence) [47]. Again, Nagashima et al recently discovered a sub‐epithelial mesenchymal cells which did not only induce gut microbiota diversity but also regulated the production of IgA which preserves gut symbiotic equilibrium [69].…”