Tianmin Cheng

The effects of total-body irradiation on the survival and skin wound healing of rats with combined radiation-wound injury

To investigate the effects of total body irradiation on the healing of skin wounds, rats were irradiated with a (60)Co gamma-ray source, in which single doses ranged from 1 to 8 Gy. After irradiation, two whole-thickness circular skin wounds, 22 mm in diameter and covering 2.5% of the total body surface area, were made immediately on the back of each animal. The average healing time for the simple wound was 18.3 +/- 2.1 days, whereas when the wound was combined with 1, 2, 3, 4, 5, and 6 Gy of radiation, the average wound healing time was delayed by 0.3, 0.8, 1.1, 3.5, 6.2, and 9.5 days, respectively. The average healing time was significantly decreased with irradiation doses exceeding 4 Gy, as compared with the healing time for the simple wound without irradiation (p < 0.05). The statistical results showed that the percentage of the unclosed wound with the increased doses in combined radiation injury was significantly proportional to the recovery time kinetics.

Recruitment of Transplanted Dermal Multipotent Stem Cells to Sites of Injury in Rats with Combined Radiation and Wound Injury by Interaction of SDF-1 and CXCR4

Abstract Zong, Z-W., Cheng, T-M., Su, Y-P., Ran, X-Z., Shen, Y., Li, N., Ai, G-P., Dong, S-W. and Xu, H. Recruitment of Transplanted Dermal Multipotent stem Cells to the Sites of Injury in Rats with Combined Radiation and Wound Injury by Interaction of SDF-1 and CXCR4. Radiat. Res. 170, 444–450 (2008). Systemic transplantation of dermal multipotent stem cells has been shown to accelerate both hematopoietic recovery and wound healing in rats with combined radiation and wound injury. In the present study, we explored the mechanisms governing the recruitment of dermal multipotent stem cells to the sites of injury in rats with combined injury. Male dermal multipotent stem cells were transplanted into female rats, and using quantitative real-time PCR for the sex-determining region of Y chromosome, it was found that the amounts of dermal multipotent stem cells in irradiated bone marrow and wounded skin were far greater than those in normal bone marrow and skin (P < 0.01). However, incubation of dermal multipotent stem cells with AMD3100 before transplantation, which specifically blocks binding of stromal cell-derived factor 1 (SDF-1) to its receptor CXCR4, diminished the recruitment of dermal multipotent stem cells to the irradiated bone marrow and wounded skin by 58 ± 4% and 60 ± 4%, respectively (P < 0.05). In addition, it was confirmed that the expression of SDF-1 in irradiated bone marrow and wounded skin was up-regulated compared to that in their normal counterparts, and in vitro analysis revealed that irradiated bone marrow and wounded skin extracts had a strong chemotactic effect on dermal multipotent stem cells but that the effect decreased significantly when dermal multipotent stem cells were preincubated with AMD3100 (P < 0.05). These data suggest that transplanted dermal multipotent stem cells were recruited more frequently to the irradiated bone marrow and wounded skin than normal bone marrow and skin and that the interactions of SDF-1 and CXCR4 played a crucial role in this process.

Transplantation of Dermal Multipotent Cells Promotes Survival and Wound Healing in Rats with Combined Radiation and Wound Injury

Abstract Shi, C., Cheng, T., Su, Y., Mai, Y., Qu, J., Ran, X., Lou, S., Xu, H. and Luo, C. Transplantation of Dermal Multipotent Cells Promotes Survival and Wound Healing in Rats with Combined Radiation and Wound Injury. Radiat. Res. 162, 56–63 (2004). Combined radiation and wound injury occurs after severe nuclear accidents that accompany explosions or nuclear attacks. High doses of ionizing radiation can cause bone marrow aplasia and delay wound healing. Combined radiation and wound injury is very complex and is more difficult to deal with than single injuries. Multipotent stem cells that have self-renewal potential and multilineage differentiation capacity are the relevant cells in regenerative medicine. To determine whether multipotent stem cells can have multiple therapeutic effects in vivo, systemic transplantation of cultured dermal multipotent cells was performed in rats with combined radiation and wound injury. The results showed that dermal multipotent cell transplantation promoted survival and accelerated both hematopoietic recovery and wound healing in rats with combined radiation and wound injury. FISH analysis using a Y-chromosome-specific probe indicated that donor dermal multipotent cells could engraft into recipient skin and bone marrow after transplantation. FACS analysis of the proportions of CD2- and CD25-positive peripheral lymphocytes indicated that dermal multipotent cell transplantation did not induce an obvious activation of allogeneic lymphocytes in vivo in 3 weeks. These data indicate that dermal multipotent cell transplantation may provide a new tool for the treatment of combined radiation and wound injuries.

Progress in Research on Radiation Combined Injury in China

Abstract Zou, Z., Sun, H., Su, Y., Cheng, T. and Luo, C. Progress in Research on Radiation Combined Injury in China. Radiat. Res. 169, 722–729 (2008). The significant feature of radiation combined injury is the occurrence of a combined effect. For decades our institute has focused on studying the key complications of radiation-burn injury, including shock, suppression of hematopoiesis and immunity, gastrointestinal damage and local refractory wound healing. Here we summarize recent advancements in elucidating the mechanisms of and potential treatments for radiation combined injury. Concerning the suppression and regeneration of hematopoiesis in radiation combined injury, mechanisms of megakaryocyte damage have been elucidated and a new type of fusion protein stimulating thrombopoiesis has been developed and is being tested in animals. With regard to the damage and repair of intestinal epithelium, the important molecular mechanisms of radiation combined injury have been clarified, and new measures to prevent and treat gastrointestinal tract injury are proposed. With respect to the difficulties encountered in wound healing, the underlying causes of radiation combined injury have been proposed, and some potential methods to accelerate wound closure are under study. Systemic experiments have been done to determine the appropriate time for eschar excision and skin grafting, and the results provided significant insight into clinical treatment of the injury. In the search for early therapeutic regimens for severe burns and radiation combined injury to prevent deterioration of injuries and to improve survival, cervical sympathetic ganglion block was used for the treatment of animals with radiation combined injury and had significant benefits. These research advancements have potential for application in on-site emergency rescue and in-hospital treatment of radiation combined injury.

Spontaneous transformation of a clonal population of dermis-derived multipotent cells in culture

It is reported that adult multipotent stem cells can undergo spontaneous transformation after long-term in vitro culture. Understanding the molecular mechanisms involved in this spontaneous transformation process can help in the design of future therapeutic applications. By far, the transformation process of adult multipotent stem cell is not well understood. In this study, a tumorigenic cell line nominated TDMC1 was established from a clonal population of rat dermis-derived multipotent cells (DMCs) following spontaneous transformation in culture. The transformed cells could produce tumors with characteristics of fibrous histocytoma when they are inoculated subcutaneously into nude mice. The molecular profiles of the nontransformed DMCs and transformed cells were analyzed by a deoxyribonucleic acid microarray. Our results showed that the overactivation of the K-ras/mitogen-activated protein kinase kinase signaling pathway played an important role in the transformation process. These data may be helpful to explain, at least in part, the possible mechanism for the malignant transformation of adult multipotent cells.

Experimental Research on the Management of Combined Radiation-Burn Injury in China

Abstract Combined radiation-burn injury can occur in people exposed to nuclear explosions, nuclear accidents or radiological terrorist attacks. Using different combined radiation-burn injury animal models, the pathological mechanisms underlying combined radiation-burn injury and effective medical countermeasures have been explored for several years in China, mainly at our institute. Targeting key features of combined radiation-burn injury, several countermeasures have been developed. Fluid transfusion and the calcium antagonist verapamil can prevent early shock and improve myocardial function after combined radiation-burn injury. Recombinant human interleukin 4 ( rhIL-4) is able to effectively reduce bacterial infection and increase intestinal immunological ability. Chitosan-wrapped human defensin 5 (HD5) and glucagon-like peptide 2 (GLP-2) nanoparticles can increase the average survival time of animals with severe combined radiation-burn injury. After treatment by cervical sympathetic ganglia block (SB), hematopoietic function is promoted and the release of inflammatory cytokines is suppressed. The optimal time for escharectomy and allo-skin grafting is 24 h after injury. Transfusion of irradiated (20 Gy) or stored (4°C, 7 days) blood improves the survival of allo-skin grafting and allo-bone marrow cells. In conclusion, as our understanding of the mechanisms of combined radiation-burn injury has progressed, new countermeasures have been developed for its treatment. Because of the complexity of its pathology and the difficulty in clinical management, further efforts are needed to improve the treatment of this kind of injury.