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The Role of Amino Acids in the Crosstalk Between Mesenchymal Stromal Cells and Neoplastic Cells in the Hematopoietic Niche.

ABSTRACT: Within the bone marrow hematopoietic cells are in close connection with mesenchymal stromal cells (MSCs), which influence the behavior and differentiation of normal or malignant lymphoid and myeloid cells. Altered cell metabolism is a hallmark of cancer, and changes in nutrient pools and fluxes are important components of the bidirectional communication between MSCs and hematological cancer cells. Among nutrients, amino acids play a significant role in cancer progression and chemo-resistance. Moreover, selected types of cancer cells are extremely greedy for glutamine, and significantly deplete the extracellular pool of the amino acid. As a consequence, this influences the behavior of MSCs in terms of either cytokine/chemokine secretion or differentiation potential. Additionally, a direct nutritional interaction exists between MSCs and immune cells. In particular, selected subpopulations of lymphocytes are dependent upon selected amino acids, such as arginine and tryptophan, for full differentiation and competence. This review describes and discusses the nutritional interactions existing in the neoplastic bone marrow niche between MSCs and other cell types, with a particular emphasis on cancer cells and immune cells. These relationships are discussed in the perspective of potential novel therapeutic strategies based on the interference on amino acid metabolism or intercellular fluxes.

SUBMITTER: Chiu M

PROVIDER: S-EPMC8278102 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Mesenchymal Stromal Cells: Role in the BM Niche and in the Support of Hematopoietic Stem Cell Transplantation.

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Project description:Haematopoietic stem cells (HSCs) are maintained by bone marrow niches in vivo1,2, but the ability of niche cells to maintain HSCs ex vivo is markedly diminished. Expression of niche factors by Nestin-GFP+ mesenchymal-derived stromal cells (MSCs) is downregulated upon culture, suggesting that transcriptional rewiring may contribute to this reduced HSC maintenance potential. Using an RNA sequencing screen, we identified five genes encoding transcription factors (Klf7, Ostf1, Xbp1, Irf3 and Irf7) that restored HSC niche function in cultured bone marrow-derived MSCs. These revitalized MSCs (rMSCs) exhibited enhanced synthesis of HSC niche factors while retaining their mesenchymal differentiation capacity. In contrast to HSCs co-cultured with control MSCs, HSCs expanded with rMSCs showed higher repopulation capacity and protected lethally irradiated recipient mice. Competitive reconstitution assays revealed an approximately sevenfold expansion of functional HSCs by rMSCs. rMSCs prevented the accumulation of DNA damage in cultured HSCs, a hallmark of ageing and replication stress. Analysis of the reprogramming mechanisms uncovered a role for myocyte enhancer factor 2c (Mef2c) in the revitalization of MSCs. These results provide insight into the transcriptional regulation of the niche with implications for stem cell-based therapies.

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