Cited2 regulates proliferation and survival in young and old mouse cardiac stem cells.

BACKGROUND: Cardiac stem cells (CSCs) exhibit age-dependent characteristics. Cited2 has been implicated in the regulation of heart development; however, there is little known about how Cited2 affects CSC aging. RESULTS: Cited2 mRNA and protein level was downregulated in aging heart tissue and CSCs. Old (O)-CSCs showed decreased differentiation and proliferation capacities as compared to Young (Y)-CSCs, the decrease in cell proliferation, increase in apoptosis, and cell cycle arrest in G0/G1 phase in CSCs are mediated by knocdown CITED2expression in (Y)-CSCs. CONCLUSIONS: Cited2 plays an important role in cell cycle progression and in maintaining the balance between CSC proliferation and apoptosis in the process of aging without influencing cell fate decisions. These findings have important implications for cell-based therapies for heart repair.

Influence of aging on the activity of mice Sca-1+CD31- cardiac stem cells.

Therapeutic application of cardiac resident stem/progenitor cells (CSC/CPCs) is limited due to decline of their regenerative potential with donor age. A variety of studies have shown that the cardiac aging was the problem of the stem cells, but little is known about the impact of age on the subgroups CSC/CPCs, the relationship between subgroups CSC/CPCs ageing and age-related dysfunction. Here, we studied Sca-1+CD31- subgroups of CSCs from younger(2~3months) and older(22~24months) age mice, biological differentiation was realized using specific mediums for 14 days to induce cardiomyocyte, smooth muscle cells or endothelial cells and immunostain analysis of differentiated cell resulting were done. Proliferation and cell cycle were measured by flow cytometry assay, then used microarray to dissect variability from younger and older mice. Although the number of CSCs was higher in older mice, the advanced age significantly reduced the differentiation ability into cardiac cell lineages and the proliferation ability. Transcriptional changes in Sca-1+CD31- subgroups of CSCs during aging are related to Vitamin B6 metabolism, circadian rhythm, Tyrosine metabolism, Complement and coagulation cascades. Taking together these results indicate that Cardiac resident stem/progenitor cells have significant differences in their proliferative, pluripotency and gene profiles and those differences are age depending.

Differentiation-Associated MicroRNA Alterations in Mouse Heart-Derived Sca-1(+)CD31(-) and Sca-1(+)CD31(+) Cells.

Cardiac resident stem/progenitor cells (CSC/CPCs) are critical to the cellular and functional integrity of the heart because they maintain myocardial cell homeostasis. Several populations of CSC/CPCs have been identified based on expression of different stem cell-associated antigens. Sca-1(+) cells in the cardiac tissue may be the most common CSC/CPCs. However, they are a heterogeneous cell population and, in transplants, clinicians might transplant more endothelial cells, cardiomyocytes, or other cells than stem cells. The purposes of this study were to (1) isolate CSC/CPCs with Lin(-)CD45(-)Sca-1(+)CD31(-) and Lin(-)CD45(-)Sca-1(+)CD31(+) surface antigens using flow-activated cell sorting; (2) investigate their differentiation potential; and (3) determine the molecular basis for differences in stemness characteristics between cell subtypes. The results indicated that mouse heart-derived Sca-1(+)CD31(-) cells were multipotent and retained the ability to differentiate into different cardiac cell lineages, but Sca-1(+)CD31(+) cells did not. Integrated analysis of microRNA and mRNA expression indicated that 20 microRNAs and 49 mRNAs were inversely associated with Sca-1(+)CD31(-) and Sca-1(+)CD31(+) subtype stemness characteristics. In particular, mmu-miR-322-5p had more targeted and inversely associated genes and transcription factors and might have higher potential for CSC/CPCs differentiation.

Identification of early myeloid progenitors as immunosuppressive cells.

Growing evidence suggests that hematopoietic stem/progenitor cells (HSPCs), precursors of mature immune cells, may play a direct role in immunosurveillance. Early myeloid progenitors are the major components of HSPCs and they often undergo extensive expansion in stress as a result of myeloid-biased hematopoiesis. Yet, the precise function of early myeloid progenitors remains unclear. Here we show that during tumor progression, mouse granulocyte/macrophage progenitors (GMPs) but not common myeloid progenitors (CMPs) are markedly expanded within the bone marrow and blood of mice. Interestingly, both GMPs and CMPs freshly isolated from either tumor-bearing or naïve animals are capable of inhibiting polyclonal stimuli- and alloantigen-induced T cell proliferation, with tumor host-derived cells having elevated activities. Strikingly, these early myeloid progenitor cells even display much stronger suppressive capacity than the classical myeloid-derived suppressive cells. Analysis of GMPs indicates that they express iNOS and can secrete high levels of NO. Further studies unusing iNOS specific inhibitors reveal that the immunosuppression of GMPs is, to a large extent, NO-dependent. GMPs can also efficiently induce regulatory T cell development. These studies demonstrate that early myeloid progenitors can act as immunosuppressive cells. This finding provides novel insights into the functional diversity and plasticity of early myeloid progenitor cells.