Gene profiling reveals association between altered Wnt signaling and loss of T-cell potential with age in human hematopoietic stem cells.

Functional decline of the hematopoietic system occurs during aging and contributes to clinical consequences, including reduced competence of adaptive immunity and increased incidence of myeloid diseases. This has been linked to aging of the hematopoietic stem cell (HSC) compartment and has implications for clinical hematopoietic cell transplantation as prolonged periods of T-cell deficiency follow transplantation of adult mobilized peripheral blood (PB), the primary transplant source. Here, we examined the gene expression profiles of young and aged HSCs from human cord blood and adult mobilized PB, respectively, and found that Wnt signaling genes are differentially expressed between young and aged human HSCs, with less activation of Wnt signaling in aged HSCs. Utilizing the OP9-DL1 in vitro co-culture system to promote T-cell development under stable Notch signaling conditions, we found that Wnt signaling activity is important for T-lineage differentiation. Examination of Wnt signaling components and target gene activation in young and aged human HSCs during T-lineage differentiation revealed an association between reduced Wnt signal transduction, increasing age, and impaired or delayed T-cell differentiation. This defect in Wnt signal activation of aged HSCs appeared to occur in the early T-progenitor cell subset derived during in vitro T-lineage differentiation. Our results reveal that reduced Wnt signaling activity may play a role in the age-related intrinsic defects of aged HSCs and early hematopoietic progenitors and suggest that manipulation of this pathway could contribute to the end goal of improving T-cell generation and immune reconstitution following clinical transplantation.

MicroRNA control of myelopoiesis and the differentiation block in acute myeloid leukaemia.

In the relatively short period of time since their discovery, microRNAs have been shown to control many important cellular functions such as cell differentiation, growth, proliferation and apoptosis. In addition, microRNAs have been demonstrated as key drivers of many malignancies and can function as either tumour suppressors or oncogenes. The haematopoietic system is not outside the realm of microRNA control with microRNAs controlling aspects of stem cell and progenitor self-renewal and differentiation, with many, if not all, haematological disorders associated with aberrant microRNA expression and function. In this review, we focus on the current understanding of microRNA control of haematopoiesis and detail the evidence for the contribution and clinical relevance of aberrant microRNA function to the characteristic block of differentiation in acute myeloid leukaemia.

Gene expression profiling of HUH7-ins: lack of a granulogenic function for chromogranin A.

Previously, the insulin producing liver cell line HUH7-ins has been shown to synthesize, store and secrete insulin in response to glucose via secretory granules. The current study characterized the gene expression profile of HUH7-ins with the aim to identify changes possibly involved in the formation of granules. Additionally, experiments were conducted to determine the influence of chromogranin A (CgA) on secretory granule biogenesis (SGB) in HUH7-ins. Expression of 165 genes were significantly changed in HUH7-ins,though interestingly the majority of secretory granule associated genes, such as the chromogranins were unchanged. CgA was over-expressed in glucose unresponsive HUH7-ins cells to test whether CgA played a role in SGB and would restore the regulated secretory phenotype. Over-expression affected neither the storage nor regulated secretion of insulin. These data suggest that SGB may by regulated at a post-transcriptional level with no evidence to indicate that CgA regulates SGB in the cell line HUH7-ins.