Abstract
Connexin 43 (Cx43) induced apoptosis has been reported in solid tumors, but the effect of Cx43 expressed by bone marrow stromal cells (BMSC) in leukemia has not been fully investigated. Manipulating Cx43 expression could be a potential therapeutic strategy for leukemia. Here, we investigate the effect of Cx43 expressed by BMSCs (human Umbilical Cord Stem Cells over-expressed CX43, Cx43-hUCSC) on leukemia cells. When co-cultured with Cx43-hUCSC, leukemia cells show significant lower growth rate with increasing apoptosis activity, and more leukemia cells enter S phase. Functional assays of fluorescence recovery after photo bleaching (FRAP) showed improved gap junctional intercellular communication (GJIC) on leukemia cells when co-cultured with Cx43-hUCSC (p < 0.01). In a mouse minimal disease model, the mean survival time and mortality rate were significantly improved in mice transplanted with Cx43-hUCSC. Our results indicate that Cx43 expressed by BMSC induces apoptosis on leukemia cells. Small molecules or other pharmaceutical approaches for modulating Cx43 expression in BMSCs could be used for delaying relapse of leukemia.
Highlights
The survival rate of leukemia has been greatly improved due to new drugs, relapse of leukemia from minimal residue disease (MRD) remains a clinical challenge
Semi-quantitative immunostaining further confirmed that majority of cells are transfected (Figure 1D) and expression of connexin 43 (Cx43) are triple comparing to expression before transfection (Figure 1E)
With bone marrow stromal cells (BMSC) over-expressing Cx43 (Cx43-human Umbilical Cord Stem Cells (hUCSC)), we evaluated the effect of increasing Cx43 on cell gap junction intercellular communication (GJIC)
Summary
The survival rate of leukemia has been greatly improved due to new drugs, relapse of leukemia from minimal residue disease (MRD) remains a clinical challenge. The remaining leukemia stem cells in bone marrow (BM) following radiotherapy and/ or chemotherapy are the primary cause for minimal residual disease (MRD) [1, 2]. There is at least 21 different human connexins have been reported [3] with a spectrum of homologs that manifest with various tissue or cell-specificity Among these connexins, connexin 43 (Cx43) is considered as a major component of gap junctions in hematopoietic tissue [4]. It has been reported that lower Cx43 expression and GJIC function deterioration in bone marrow cells associated with leukemia development www.impactjournals.com/oncotarget [9, 13]. It has been speculated that Cx43 expression in bone marrow stromal cells (BMSC) improves the GJIC between BMSC and leukemia cells in BM to limit leukemia cell proliferation. We present evidence to show that Cx43 over-expression in BMSCs improves GJIC and induces apoptosis on leukemia cells through caspase 3 and 7
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