Dataset Information

SIRT1 is dispensable for maturation of hematopoietic stem cell in the bone marrow niche.

ABSTRACT: Sirtuin 1 (SIRT1) is a histone deacetylase implicated in stem cell homeostasis. Conditional Sirt1 deletion in the hematopoietic stem and progenitor system promotes hematopoietic stem and progenitor cell (HSPC) expansion under stress conditions. In addition, SIRT1 activators modulate the capacity and HSPC numbers in the bone marrow (BM). To investigate the role of SIRT1 in the BM niche, a conditional Sirt1 deletion in the BM niche was generated in a mouse model for the present study. Multicolor flow cytometric analyses were performed to determine HSC cell populations. Using 5-fluorouracil-induced proliferative stress, a survival curve was produced. In the present study, Sirt1 deletion in the BM niche demonstrated that the production of mature blood cells, lineage distribution within hematopoietic organs and frequencies of HSPC populations were comparable to those of controls. Additionally, Sirt1 deletion in the BM niche did not perturb HSC maturation under stress induced by transplantation. Therefore, these observations suggest that SIRT1 serves a dispensable role in HSC maturation in the BM niche.

SUBMITTER: Park SM

PROVIDER: S-EPMC6704581 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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SIRT1 is dispensable for maturation of hematopoietic stem cell in the bone marrow niche.

Park Su Min SM Kim Jayoung J Hong Chae Mi CM Shin Dong Hoon DH Kim Jee Yeon JY Park Do Youn DY Sohn Dong Hyun DH Kim Yun Hak YH Kwon Sang-Mo SM Kim Jae Ho JH Bae Sun Sik SS Kim Koanhoi K Kim Chi Dae CD Kang Chi-Dug CD Lee Dongjun D

Experimental and therapeutic medicine 20190725 3

Sirtuin 1 (SIRT1) is a histone deacetylase implicated in stem cell homeostasis. Conditional <i>Sirt1</i> deletion in the hematopoietic stem and progenitor system promotes hematopoietic stem and progenitor cell (HSPC) expansion under stress conditions. In addition, SIRT1 activators modulate the capacity and HSPC numbers in the bone marrow (BM). To investigate the role of SIRT1 in the BM niche, a conditional <i>Sirt1</i> deletion in the BM niche was generated in a mouse model for the present study ...[more]

PMID: 31452717

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Project description:Hematopoietic stem cells (HSCs) primarily reside in the bone marrow, where they receive external cues from their local microenvironment. The complex milieu of biophysical cues, cellular components and cell-secreted factors regulates the process by which HSC produce the blood and immune system. We previously showed direct coculture of primary murine hematopoietic stem and progenitor cells with a population of marrow-derived mesenchymal stromal and progenitor cells (MSPCs) in a methacrylamide-functionalized gelatin (GelMA) hydrogel improves hematopoietic progenitor maintenance. However, the mechanism by which MSPCs influenced HSC fate decisions remained unknown. Herein, we report the use of proteomic analysis to correlate HSC phenotype to a broad candidate pool of 200 soluble factors produced by combined mesenchymal and hematopoietic progeny. Partial least squares regression (PLSR), along with an iterative filter method, identified TGFβ-1, MMP-3, c-RP and TROY as positively correlated with HSC maintenance. Experimentally, we then observe exogenous stimulation of HSC monocultures in GelMA hydrogels with these combined cytokines increases the ratio of hematopoietic progenitors to committed progeny after a 7-day culture 7.52 ± 3.65-fold compared to non-stimulated monocultures. Findings suggest a cocktail of the downselected cytokines amplifies hematopoietic maintenance potential of HSCs beyond that of MSPC-secreted factors alone. This work integrates empirical and computation methods to identify cytokine combinations to improve HSC maintenance within an engineered HSC niche, suggesting a route toward identifying feeder-free culture platforms for HSC expansion. Insight Hematopoietic stem cells within an artificial niche receive maintenance cues in the form of soluble factors from hematopoietic and mesenchymal progeny. Applying a proteomic regression analysis, we identify a reduced set of soluble factors correlated to maintenance of a hematopoietic phenotype during culture in a biomaterial model of the bone marrow niche. We identify a minimum factor cocktail that promotes hematopoietic maintenance potential in a gelatin-based culture, regardless of the presence of mesenchymal feeder cells. By combining empirical and computational methods, we report an experimentally feasible number of factors from a large dataset, enabling exogenous integration of soluble factors into an engineered hematopoietic stem cell for enhanced maintenance potential of a quiescent stem cell population.

Project description:Abstract: The crosstalk between hematopoietic stem cells (HSC) and bone marrow (BM) microenvironment is critical for homeostasis and hematopoietic regeneration in response to blood formation emergencies after injury, and has been associated with leukemia transformation and progression. Intercellular signals by the BM stromal cells in the form of cell-bound or secreted factors, or by physical interaction, regulate HSC localization, maintenance, and differentiation within increasingly defined BM HSC niches. Gap junctions (GJ) are comprised of arrays of membrane embedded channels formed by connexin proteins, and control crucial signaling functions, including the transfer of ions, small metabolites, and organelles to adjacent cells which affect intracellular mechanisms of signaling and autophagy. This review will discuss the role of GJ in both normal and leukemic hematopoiesis, and highlight some of the most novel approaches that may improve the efficacy of cytotoxic drugs. Connexin GJ channels exert both cell-intrinsic and cell-extrinsic effects on HSC and BM stromal cells, involved in regenerative hematopoiesis after myelosuppression, and represent an alternative system of cell communication through a combination of electrical and metabolic coupling as well as organelle transfer in the HSC niche. GJ intercellular communication (GJIC) in the HSC niche improves cellular bioenergetics, and rejuvenates damaged recipient cells. Unfortunately, they can also support leukemia proliferation and survival by creating leukemic niches that provide GJIC dependent energy sources and facilitate chemoresistance and relapse. The emergence of new strategies to disrupt self-reinforcing malignant niches and intercellular organelle exchange in leukemic niches, while at the same time conserving normal hematopoietic GJIC function, could synergize the effect of chemotherapy drugs in eradicating minimal residual disease. An improved understanding of the molecular basis of connexin regulation in normal and leukemic hematopoiesis is warranted for the re-establishment of normal hematopoiesis after chemotherapy.

Dataset Information

SIRT1 is dispensable for maturation of hematopoietic stem cell in the bone marrow niche.

Publications

SIRT1 is dispensable for maturation of hematopoietic stem cell in the bone marrow niche.

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