Metabolism of tissue macrophages in homeostasis and pathology

Cellular metabolism orchestrates the intricate use of tissue fuels for catabolism and anabolism to generate cellular energy and structural components. The emerging field of immunometabolism highlights the importance of cellular metabolism for the maintenance and activities of immune cells. Macrophages are embryo- or adult bone marrow-derived leukocytes that are key for healthy tissue homeostasis but can also contribute to pathologies such as metabolic syndrome, atherosclerosis, fibrosis or cancer. Macrophage metabolism has largely been studied in vitro. However, different organs contain diverse macrophage populations that specialize in distinct and often tissue-specific functions. This context specificity creates diverging metabolic challenges for tissue macrophage populations to fulfill their homeostatic roles in their particular microenvironment and conditions their response in pathological conditions. Here, we outline current knowledge on the metabolic requirements and adaptations of macrophages located in tissues during homeostasis and selected diseases.

A distinct CD115- erythro-myeloid precursor present at the maternal-embryonic interface and in the bone marrow of adult mice

During ontogeny, macrophages develop from CD115+ precursors, including erythro-myeloid progenitors (EMP). EMP arise in the embryonic yolk sac, the primary site of early haematopoiesis. In adults, CD115+ bone marrow-derived monocytes represent essential macrophage precursors. Herein, we identify a CD115- macrophage precursor within the adult bone marrow that is unrelated to the classical monocyte lineage but rather shares transcriptomic and functional characteristics of embryonic EMP. These EMPROR (for Erythro Myeloid Precursor) cells are capable of efficiently generating macrophages in disease settings. During early development, EMPROR cells were largely absent from the yolk sac but were instead found at the embryonic-maternal interface in the uterine wall. Unexpectedly, the latter site contains robust haematopoietic activity and harbours defined embryonic haematopoietic progenitor cells, including classical CD115+ EMP. Our data suggest the existence of an alternative pathway of macrophage generation in the adult. Further, we uncover a hitherto unknown site of earliest blood cell development.

Stem Cells: Novel Technologies, Therapies and Industrial Models

Stem cells are a kind of cells with the ability of self-renewal and multi-directional differentiation potential. A variety of stem cells or progenitor cells have been shown to be efficacy in the treatment of some refractory diseases. The mesenchymal stem cells (MSCs) are derived from mesoderm and have the characteristics of differentiation into three germ layers and immune regulation, which means that these cells are suitable for either autologous or allogeneic treatment and are ideal cells for regenerative medicine. MSCs can be isolated from various tissue types, including the bone marrow, fat, and perinatal tissues. From the perspective of ethics, medicine and cell engineering, adult bone marrow and adipose MSCs cannot be used as a mass production source of conventional treatment. Perinatal tissue, including umbilical cord, amniotic fluid and placenta, is a rich source of MSCs with strong immunosuppressive and proangiogeneic activities. These stem cells bring new hope for disease treatment. This paper reviews the research progress of stem cells as novel technology, novel therapies and industrial model in the field of regenerative medicine.

B1a and B2 cells are characterized by distinct CpG modification states at DNMT3A-maintained enhancers

The B1 and B2 lineages of B cells contribute to protection from pathogens in distinct ways. The role of the DNA CpG methylome in specifying these two B-cell fates is still unclear. Here we profile the CpG modifications and transcriptomes of peritoneal B1a and follicular B2 cells, as well as their respective proB cell precursors in the fetal liver and adult bone marrow from wild-type and CD19-Cre Dnmt3a floxed mice lacking DNMT3A in the B lineage. We show that an underlying foundational CpG methylome is stably established during B lineage commitment and is overlaid with a DNMT3A-maintained dynamic methylome that is sculpted in distinct ways in B1a and B2 cells. This dynamic DNMT3A-maintained methylome is composed of novel enhancers that are closely linked to lineage-specific genes. While DNMT3A maintains the methylation state of these enhancers in both B1a and B2 cells, the dynamic methylome undergoes a prominent programmed demethylation event during B1a but not B2 cell development. We propose that the methylation pattern of DNMT3A-maintained enhancers is determined by the coincident recruitment of DNMT3A and TET enzymes, which regulate the developmental expression of B1a and B2 lineage-specific genes.