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MiR-125a enhances self-renewal, lifespan, and migration of murine hematopoietic stem and progenitor cell clones.

ABSTRACT: Expansion of hematopoietic stem cells (HSCs) is a 'holy grail' of regenerative medicine, as successful stem cell transplantations depend on the number and quality of infused HSCs. Although many attempts have been pursued to either chemically or genetically increase HSC numbers, neither clonal analysis of these expanded cells nor their ability to support mature blood lineages has been demonstrated. Here we show that miR-125a, at the single cell level, can expand murine long-term repopulating HSCs. In addition, miR-125a increases clone longevity, clone size and clonal contribution to hematopoiesis. Unexpectedly, we found that miR-125a expanded HSCs clones were highly homogenously distributed across multiple anatomical sites. Interestingly, these miR-125a overexpressing cells had enhanced mobility and were more frequently detected in the spleen. Our study reveals a novel, cell-intrinsically controlled mechanism by which HSC migration is regulated.

SUBMITTER: Wojtowicz EE

PROVIDER: S-EPMC6423273 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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MiR-125a enhances self-renewal, lifespan, and migration of murine hematopoietic stem and progenitor cell clones.

Wojtowicz Edyta Ewa EE Broekhuis Mathilde Johanna Christina MJC Weersing Ellen E Dinitzen Alexander A Verovskaya Evgenia E Ausema Albertina A Ritsema Martha M Zwart Erik E de Haan Gerald G Bystrykh Leonid V LV

Scientific reports 20190318 1

Expansion of hematopoietic stem cells (HSCs) is a 'holy grail' of regenerative medicine, as successful stem cell transplantations depend on the number and quality of infused HSCs. Although many attempts have been pursued to either chemically or genetically increase HSC numbers, neither clonal analysis of these expanded cells nor their ability to support mature blood lineages has been demonstrated. Here we show that miR-125a, at the single cell level, can expand murine long-term repopulating HSCs ...[more]

PMID: 30886165

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Project description:BackgroundRecently, many microRNAs have been found to be involved in the cancer progression including miR-125a. However, the underlying mechanisms of miR-125a in gastric cancer (GC) remain to be completely elucidated.ObjectiveThe study was to investigate the functional role of miR-125a and the expression relevance of signal transducer and activator of transcription 3 (STAT3) and hyaluronan synthase 1 (HAS1).MethodCCK-8 assay, scratch wound healing and transwell assay were conducted to identify the functional role of miR-125a in GC. In addition, using bioinformatics analysis, the target regulation relationship was found in STAT3 and miR-125a. To confirm the relationship, luciferase reporter assay was performed. More importantly, quantitative polymerase chain reaction and western blot assay were carried out to determine the association among miR-125a, STAT3 and HAS1 in GC cells.ResultsOverexpressed miR-125a inhibited the migration and invasion of GC cells through scratch wound healing and transwell assay, and its knockdown displayed adverse effects, but the viability of GC cells did not show significant difference using CCK-8 assay. In addition, we identified that the knockdown of STAT3 or HAS1 remarkably suppressed the migration and invasion abilities of GC cells. Using bioinformatics analysis, miRTar, in particular, indicated that the 3'-untranslated region of STAT3 binds to miR-125a with a high score. Subsequently, we also verified that STAT3 was a target of miR-125a via luciferase reporter assay. Furthermore, we found that upregulated miR-125a expression could conspicuously constrain STAT3 expression at both protein and mRNA levels in MKN45 and NCI-N87 cells using quantitative polymerase chain reaction and Western blot assay, but no significant difference had been found in SGC 7901 cells. To further identify the regulatory relationship between miR-125a and STAT3, downregulation of miR-125a in MKN45 and NCI-N87 cells was carried out, which showed that the protein and mRNA expression levels of STAT3 were declined in two cell lines. Finally, we observed that upregulated miR-125a could lead to the decrease of HAS1 at protein and mRNA levels, whereas its knockdown revealed opposite effects. Meanwhile, we noticed that overexpression of STAT3 could induce the escalation of HAS1 at protein and mRNA expression levels and its knockdown exhibited the adverse outcomes.ConclusionThese findings indicated that miR-125a may control the HAS1 expression in GC progression by targeting STAT3, which is likely to facilitate a better understanding of the regulation mechanisms of miR-125a in GC.

Dataset Information

MiR-125a enhances self-renewal, lifespan, and migration of murine hematopoietic stem and progenitor cell clones.

Publications

MiR-125a enhances self-renewal, lifespan, and migration of murine hematopoietic stem and progenitor cell clones.

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