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Single-cell RNA sequencing analysis reveals the relationship of bone marrow and osteopenia in type 1 diabetic mice

ABSTRACT: Type 1 diabetes (T1D) is a multifactorial autoimmune disease characterized by the destruction of pancreatic beta (β) cells and resultant hyperglycaemia. Broad knowledge about the genetics, epidemiology, and clinical management of T1D has been achieved, but the cell varieties in the bone marrow during T1D remain poorly understood. Here, we performed a single-cell RNA sequencing analysis of whole bone marrow cells from healthy (group C) and STZ-induced T1D (group D) mice for the first time, presenting a profile of the bone marrow cells and revealing the changes in immune cells in bone marrow. The bone marrow cells in both groups C and D were divided into 12 clusters, and there were 249 differentially expressed genes (DEGs). Compared with group C, the proportion of CD45+ immune cells in group D was not changed much. However, the diversity of CD45+ immune cells between groups C and D were greatly affected. There was a large increase in the proportion of bone marrow neutrophils (BM-neutrophils) and a large decrease in the proportion of B lymphocytes in group D. Furthermore, it was confirmed by X-ray and micro-CT analyses that osteopenia occurred in group D mice. Finally, we investigated the correlation between immune cells and osteopenia. The results of single-cell flow cytometry and correlation analysis showed that the ratio of BM-neutrophils/B lymphocytes was negatively correlated with osteopenia in T1D mice. Thus, precise regulation of the immune cells in the bone marrow may contribute to a better understanding of the treatment of T1D and the prevention of T1D-induced osteopenia.

ORGANISM(S): Mus musculus

PROVIDER: GSE182986 | GEO | 2021/08/31

REPOSITORIES: GEO

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Project description:The CCAAT/enhancer-binding proteins (CEBPs) are transcription factors involved in hematopoietic cell development and induction of several inflammatory mediators. Here, we generated CEBP-beta (CEBPB) and CEBP-epsilon (CEBPE) double-knockout (bbee) mice and compared their phenotypes to those of single-deficient (bbEE and BBee) and wild-type (BBEE) mice. The bbee mice were highly susceptible to fatal infections and died within 2-3 months. Morphologically, their neutrophils were blocked at the myelocytes/metamyelocytes stage, and clonogenic assays of bone marrow cells indicated a significant decrease in the number of myeloid colonies of the bbee mice. In addition, the proportion of hematopoietic progenitor cells [Lin(-)Sca1(+)c-Kit(+)] in the bone marrow of the bbee mice was significantly increased, reflecting the defective differentiation of the myeloid compartment. Furthermore, microarray expression analysis of lipopolysaccharide (LPS)- and interferon-gamma (IFN-gamma)-activated bone marrow-derived macrophages from bbee compared to single knockout mice revealed decreased expression of essential immune response-related genes and networks, including some direct CEBP targets such as Marco and Clec4e. Overall, the phenotype of the bbee mice is distinct from either the bbEE or BBee mice, demonstrating that both transcription factors are crucial for the maturation of neutrophils and macrophages, as well as the innate immune system, and can at least in part compensate for each other in the single knockout mice. To rule out the regulatory influence of both CEBPB and CEBPE on macrophage-related genes, expression analysis of bone marrow-derived macrophages was performed. Macrophages were derived from murine bone marrow with the use of murine M-CSF. The macrophages were stimulated with both LPS (100 ng) and IFN-gamma (100 ng) for 24h, and RNA was extracted for array analysis. Overall, RNA was extracted from stimulated macrophages of one WT mouse, one CEBPB-KO mouse, one CEBPE-KO mouse and one double-KO mouse.

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Single-cell RNA sequencing analysis reveals the relationship of bone marrow and osteopenia in type 1 diabetic mice

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