Effects of signaling pathway inhibitors on hematopoietic stem cells.

ABSTRACT

While there are numerous small molecule inhibitory drugs available for a wide range of signalling pathways, at present, they are generally not used in combination in clinical settings. Previous reports have reported that the effects of glycogen synthase kinase (GSK)3ß, p38MAPK, mTOR and histone deacetylase signaling combined together to suppress the stem­like nature of hematopoietic stem cells (HSCs), driving these cells to differentiate, cease proliferating and thereby impairing normal hematopoietic functionality. The present study aimed to determine the effect of HDACs, mTOR, GSK­3ß and p38MAPK inhibitor combinations on the efficient expansion of HSCs using flow cytometry. Moreover, it specifically aimed to determine how inhibitors of the GSK3ß signaling pathway, in combination with inhibitors of P38MAPK and mTOR signaling or histone deacetylase (HDAC) inhibitors, could affect HSC expansion, with the goal of identifying novel combination strategies useful for the expansion of HSCs. The results indicated that p38MAPK and/or GSK3ß inhibitors increased Lin­ cell and Lin­Sca­1+c­kit+ (LSK) cell numbers in vitro. Taken together, these results suggested that a combination of p38MAPK and GSK3ß signaling may regulate HSC differentiation in vitro. These findings further indicated that the suppression of p38MAPK and/or GSK3ß signalling may modulate HSC differentiation and self­renewal to enhance HSC expansion.