Inflammatory bowel disease: Moving toward a stem cell-based therapy

The incidence and prevalence of Crohn's disease (CD) and ulcerative colitis (UC), the two major forms of inflammatory bowel diseases (IBD), are rising in western countries. The modern hygienic lifestyle is probably at the root of a disease where, in genetically susceptible hosts, the intestinal commensal flora triggers dysregulated immune and inflammatory responses. Current therapies ranging from anti-inflammatory drugs to immunosuppressive regimens, remain inadequate. Advances in our understanding of the cell populations involved in the pathogenetic processes and recent findings on the regenerative, trophic and immunoregulatory potential of stem cells open new paths in IBD therapy. Hematopoietic and mesenchymal stem cells are catalyzing the attention of IBD investigators. This review highlights the pivotal fi ndings for stem cell-based approaches to IBD therapy and collects the encouraging results coming in from clinical trials.

Fetal kidney stem cells ameliorate cisplatin induced acute renal failure and promote renal angiogenesis

AIM: To investigate whether fetal kidney stem cells(f KSC) ameliorate cisplatin induced acute renal failure(ARF) in rats and promote renal angiogenesis.METHODS: The f KSC were isolated from rat fetuses of gestation day 16 and expanded in vitro up to 3rd passage. They were characterized for the expression of mesenchymal and renal progenitor markers by flow cytometry and immunocytochemistry, respectively. The in vitro differentiation of f KSC towards epithelial lineage was evaluated by the treatment with specific induction medium and their angiogenic potential by matrigel induced tube formation assay. To study the effect of f KSC in ARF, f KSC labeled with PKH26 were infused in rats with cisplatin induced ARF and, the blood and renal tissues of the rats were collected at different time points. Blood biochemical parameters were studied to evaluate renal function. Renal tissues were evaluated for renal architecture, renal cell proliferation and angiogenesis by immunohistochemistry, renal cell apoptosis by terminal deoxynucleotidyl transferase nickend labeling assay and early expression of angiogenic molecules viz. vascular endothelial growth factor(VEGF), hypoxia-inducible factor(HIF)-1α and endothelial nitric oxide synthase(eN OS) by western blot.RESULTS: The fK SC expressed mesenchymal markers viz. CD29, CD44, CD73, CD90 and CD105 as well asrenal progenitor markers viz. Wt1, Pax2 and Six2. They exhibited a potential to form CD31 and Von Willebrand factor expressing capillary-like structures and could be differentiated into cytokeratin(CK)18 and CK19 positive epithelial cells. Administration of fK SC in rats with ARF as compared to administration of saline alone, resulted in a significant improvement in renal function and histology on day 3(2.33 ± 0.33 vs 3.50 ± 0.34, P < 0.05) and on day 7(0.83 ± 0.16 vs 2.00 ± 0.25, P < 0.05). The infused PKH26 labeled fK SC were observed to engraft in damaged renal tubules and showed increased proliferation and reduced apoptosis(P < 0.05) of renal cells. The kidneys of fK SC as compared to saline treated rats had a higher capillary density on day 3 [13.30 ± 1.54 vs 7.10 ± 1.29, capillaries/high-power fields(HPF), P < 0.05], and on day 7(21.10 ± 1.46 vs 15.00 ± 1.30, capillaries/HPF, P < 0.05). In addition, kidneys of fK SC treated rats had an upregulation of angiogenic proteins hypoxia-inducible factor-1α, VEGF and eN OS on day 3(P < 0.05).CONCLUSION: Our study shows that fK SC ameliorate cisplatin induced ARF in rats and promote renal angiogenesis, which may be an important therapeutic mechanism of these stem cells in the disease.

Autologous cytokine-induced killer cells combined with chemotherapy in the treatment of advanced colorectal cancer: a randomized control study

Objective：To evaluate the ef icacy of autologous cytokine-induced kil er （CIK） cells transfusion combined with chemotherapy in patients suf ered from advanced colorectal cancer. Methods： Sixty untreated patients with advanced colorectal cancer were randomly divided into two groups. The 30 patients in the control group received chemotherapy with the regimen of xeloda plus oxiplatin （XELOX）. The 30 patients in the trial group were treated with chemotherapy （XELOX） in combination with autologous CIK celltransfusion. T-lymphocyte subgroups were separated and measured by flow cytometry quality of life （QOL） was determined by EORTC QLQ-C30. The short-term curative ef ect was evaluated via imaging examina-tions. The patients’ median progression free survival time was estimated by Kaplan-Meier. Results：The T-lymphocyte im-mune activity was improved in patients received autologous CIK celltransfusion than those treated with chemotherapy alone. The subgroup of CD3＋CD56＋T lymphocyte was significantly increased （4.28 ± 0.45 vs 10.14 ± 1.02, P=0.01）. Short-term ef icacy evaluation revealed that there was no significant dif erence in terms of objective response rate （ORR） between the two groups, but the disease control rate （DCR） was markedly increased （86.7%vs 56.7%, P=0.020） in the group treated by chemotherapy plus CIK cells compared to the group treated with chemotherapy alone. The progression free survival time was 8.64 months （ 95%CI 6.25-9.75 months） in control group and 10.15 months （ 95%CI 7.48-12.52 months） in trial group. Compared to patients in control group, the patients in trial group had significantly longer progression-free survival （P=0.046）. The QOL assessment suggested the QOL in trial group was obviously improved than that in the control group. Compared with the control group, patients treated with autologous CIK celltransfusion scored more in the area of physical function and general health status, while the symptomatic scores in terms of pain, fatigue, nausea and vomiting and diarrhea were significantly reduced. Conclusion：Autologous CIK celltransfusion combined with chemotherapy can ef ectively enhance the immune activity of T-lymphocytes, prevent disease progression and improve the progression-free survival and QOL in patients with advanced colorectal cancer.