Inhibition of Soluble Stem Cell Factor Promotes Intestinal Mucosal Repair.

BACKGROUND: Incidences of inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, are escalating worldwide and can be considered a global public health problem. Given that the gold standard approach to IBD therapeutics focuses on reducing the severity of symptoms, there is an urgent unmet need to develop alternative therapies that halt not only inflammatory processes but also promote mucosal repair. Previous studies have identified increased stem cell factor (SCF) expression in inflamed intestinal mucosal tissues. However, the role that SCF plays in mediating intestinal inflammation and repair has not been explored. METHODS: Changes in the expression of SCF were evaluated in the colonic tissue of healthy mice and during dextran sodium sulfate (DSS)-induced colitis. Furthermore, mucosal wound healing and colitis severity were analyzed in mice subjected to either mechanical biopsy or DSS treatment, respectively, following intestinal epithelial cell-specific deletion of SCF or anti-SCF antibody administration. RESULTS: We report robust expression of SCF by intestinal epithelial cells during intestinal homeostasis with a switch to immune cell-produced SCF during colitis. Data from mice with intestinal epithelial cell-specific deletion of SCF highlight the importance of immune cell-produced SCF in driving the pathogenesis of colitis. Importantly, antibody-mediated neutralization of total SCF or the specific SCF248 isoform decreased immune cell infiltration and enhanced mucosal wound repair following biopsy-induced colonic injury or DSS-induced colitis. CONCLUSIONS: These data demonstrate that SCF functions as a pro-inflammatory mediator in mucosal tissues and that specific neutralization of SCF248 could be a viable therapeutic option to reduce intestinal inflammation and promote mucosal wound repair in individuals with IBD.

Our investigation demonstrates that blocking cleavable SCF248 isoform by administration of specific stem cell factor antibodies enhances healing of the intestinal mucosa and restores critical barrier function, suggesting an alternative therapeutic option to treat individuals with active IBD.

Geniposide enhances melanogenesis by stem cell factor/c-Kit signalling in norepinephrine-exposed normal human epidermal melanocyte.

Geniposide is an iridoid glycoside isolated from the fruit of Gardenia jasminoides Ellis used as a Chinese traditional medicine for treatment of generalized vitiligo. Stem cell factor from keratinocyte recognizes and activates its receptor c-kit carried by melanocyte to potent enhance melanocytic melanogenesis that can be suppressed by norepinephrine. This study addresses the action and mechanism of geniposide enhancing melanogenesis in norepinephrine-exposed normal human epidermal melanocyte. Flow cytometry results from this study exhibited the augmentation effect of geniposide on production of c-kit receptor by norepinephrine-exposed normal human epidermal melanocyte. However, geniposide did not affect the production of stem cell factor by norepinephrine-exposed normal human epidermal keratinocyte assessed by cellular enzyme-linked immunosorbent assay (ELISA). ELISA indicated that at the presence of stem cell factor, geniposide was capable of elevating the level of extracellular signal-regulated kinase 1/2 phosphorylation within norepinephrine-exposed normal human epidermal melanocyte, which is known to be involved in stem cell factor/c-kit downstream signalling. And inhibition of c-kit with inhibitory antibody K44.2 completely blocked the increase in geniposide-stimulated extracellular signal-regulated kinase 1/2 phosphorylation. In addition, spectrophotometry demonstrated the enhancement effect of geniposide on melanogenesis (tyrosinase activity and melanin production) in norepinephrine-exposed normal human epidermal melanocyte at the presence of stem cell factor, which was blocked by c-kit inhibitory antibody K44.2. Data from this study suggest that geniposide can enhance melanogenesis by stem cell factor/c-kit signalling in which the expression of c-kit receptor is augmented in norepinephrine-exposed normal human epidermal melanocyte.

Human stem cell factor-antibody [anti-SCF] enhances chemotherapy cytotoxicity in human CD34+ resistant myeloid leukaemia cells.

Acute myeloid leukaemia (AML) is a heterogenous malignant disease with diverse biological features in which disease progression at the level of CD34+ cells has a major impact on the resistance to chemotherapy and relapse. The AML blast cells in these elderly patients are often characterised by several unfavourable covariates that predict the poor treatment outcome, including high stem cell marker CD34 expression, minimally or undifferentiated features, high P-glycoprotein expression, high bcl-2/bax ratio, unfavourable karyotype and more frequent internal tandem duplications (ITDs) and mutations of class III receptor-type tyrosine kinase for key haematopoietic cytokines: Flt-3 (receptor for Flt-ligand), c-kit (receptor for stem cell factor) and fms (receptor for M-CSF). Testing the new and more specific molecular-targeted therapeutic approaches in CD34+ AML cells can provide the basis for a more effective combined molecular/chemotherapy regimen and may consequently improve the treatment outcome in elderly AML patients. Therefore, the present study was performed to evaluate whether stem cell factor-antibody (anti-SCF) can enhance the efficacy of the two main chemotherapeutic drugs used in AML therapy: cytarabine and daunorubicin at low doses in human-resistant CD34+ AML cells, in an attempt to identify a novel effective regimen with tolerable side-effects for elderly AML patients. The effect of anti-SCF on each of the two chemotherapeutic drugs-induced apoptosis and necrosis was investigated in KG1a human-resistant CD34+ AML cells expressing P-glycoprotein to determine its enhancing activity. Anti-SCF has significantly enhanced the low dose cytarabine- and daunorubicin-induced apoptosis+necrosis in KG1a CD34+ AML cells from 12.0+/-1.7 to 40.9+/-5.9% and from 16.3+/-0.9 to 48.9+/-1.0%, respectively, p<0.01. It has also exerted its significant enhancement activity on the low dose cytarabine- and daunorubicin-induced apoptosis+necrosis in KG1a CD34+ AML cells in the presence of SCF, p<0.05. Anti-SCF has significantly enhanced the low dose cytarabine- and daunorubicin-induced bcl-2 reduction in KG1a CD34+ AML cells from 26.7+/-0.6 to 64.6+/-1.0% and from 59.8+/-3.1 to 80.1+/-7.9%, respectively, p<0.01. The addition of SCF has not altered the low dose cytarabine- and daunorubicin-induced bcl-2 reduction in KG1a CD34+ AML cells (Table 4). Anti-SCF has also significantly enhanced the low dose cytarabine- and daunorubicin-induced bcl-2 reduction in KG1a CD34+ AML cells in the presence of SCF, p<0.05. The unique potent enhancing activity of anti-SCF on low dose chemotherapy-induced apoptosis and necrosis in extremely resistant AML cells suggest a novel promising role for the treatment of elderly AML patients. Further studies are warranted to evaluate a similar enhancing effect for anti-SCF in blast cells from elderly AML patients in primary cultures before its introduction in a pilot clinical study. In conclusion, the combination of anti-SCF and the low dose cytarabine provides a promising solution for the dilemma of therapy in elderly AML patients.