Page 62 - 2019_09-HaematologicaMondo-web

Z. Zhang et al.
ABCDE
FGHIJ
Figure 6. The effect of aging on hematopoietic stem and progenitor cells (HSPC) in Kitlfl/fl and Adipoq-Cre+;Kitlfl/fl mice. (A) Body weight of Kitlfl/fl and Adipoq-Cre+;Kitlfl/fl (n=6) male mice at three [n=9 and 10 for control and knock-out (KO), respectively] and ten (n=6 and 5 for control and KO, respectively) months of age. (B-J) Flow cytometric analyses of bone marrow from Kitlfl/fl and Adipoq-Cre+;Kitlfl/fl (n=6) male mice at three (n=9 and 10 for control and KO, respectively) and ten (n=6 and 5 for control and KO, respectively) months of age, showing total cellularity (B), LSK number (C), MP number (D), CMP number (E), MEP number (F), GMP number (G), CLP number (H), MEP/GMP ratio (I), and CLP/CMP ratio (J). Data are presented as mean±Standard Deviation. Two-way ANOVA followed by multiple comparison using Tukey's correction was performed. (Top) P-values for interaction and between groups. *P<0.05; **P<0.01; ***P<0.001 between 3M and 10M mice in indicated genotypes.
being housed at 30°C for one month, Adipoq-Cre+;Kitlfl/fl mice had similar body weight, body composition, and MAT mass to Kitlfl/fl mice (Online Supplementary Figure S9E and F). Loss of adipose SCF eliminated the rise in MEP/GMP ratio (Online Supplementary Figure S9G) but fur- ther augmented the increase in CLP/CMP ratio (Online Supplementary Figure S9H). Collectively, these data show that adipocyte-derived SCF mediates part of the environ- mental effects, particularly those via the β3-adrenergic sig- naling, on HSPC function.
MAT-provided stem cell factor in the aged hematopoietic stem and progenitor cell compartment
Aging-related changes in the hematopoietic system can be attributed to cell-intrinsic and microenvironmental alterations.54 MAT expands as a function of age in both rodents and humans,27 we then sought to determine whether SCF from MAT contributes to altered HSPC func- tion during aging. Young (3 months old) and middle-aged (10 months old) male mice were analyzed; we did not observe any difference in body weight between Kitlfl/fl and Adipoq-Cre+;Kitlfl/fl mice at either age (Figure 6A). Aging slightly decreased BM cellularity in control mice, which was further down-regulated by the loss of adipose SCF (Figure 6B). Strikingly, the expansion of LSK and various myeloid progenitors including CMP, MEP, and GMP observed in middle-aged mice was totally abolished in Adipoq-Cre+;Kitlfl/fl mice (Figure 6C-G). There were more CLP in 10-month old mice than in 3-month old mice, but there was no difference in these changes between geno- types (Figure 6H). Aging increased the ratios of both MEP to GMP and CLP to CMP; however, Kitlfl/fl and Adipoq- Cre+;Kitlfl/fl mice showed similar extent of increase as the interaction effect was not statistically significant (Figure 6I
and J). These data demonstrate that SCF, as a MAT niche factor, is essential for the phenotypic expansion of HSC and myeloid progenitors during aging.
Discussion
Hematopoietic cytokines support the developmental processes of blood cells, at least partially through rewiring the cellular metabolism. Meanwhile, many of these cytokines also act directly on diverse metabolic tissues and cells. For example, erythropoietin improves glycemic control and insulin sensitivity, prevents obesity by acting on the hypothalamus, and attenuates adipose tissue inflammation.55 Granulocyte-macrophage colony-stimu- lating factor regulates lipid metabolism in the liver.56 Interleukin 4 inhibits adipogenesis, promotes lipolysis, and also disposes glucose by enhancing insulin action.57,58 Interestingly, a specific hemopoietin cocktail composed of SCF, FLT3 ligand, IL-6, and vascular endothelial growth factor together with bone morphogenic protein 7 induces efficient differentiation of human pluripotent stem cells into functional brown adipocytes.37 Our previous work showed that the expression of SCF in BAT is sensitive to food availability and environmental temperature.38 SCF overexpression activates thermogenesis in BAT and reduces weight gain, while Kit mutant mice become obese as a result of reduced energy expenditure.38 Consistently with these previous findings, in this study we found that adipose-derived SCF was required for thermogenic gene expression in cultured adipocytes, demonstrating a cell- autonomous effect of SCF. However, no changes in UCP1 expression, body weight, or glucose metabolism were observed in Adipoq-Cre+;Kitlfl/fl mice, suggesting a possible
1740
haematologica | 2019; 104(9)