骨髓间充质干细胞对胸腺辐射凋亡的作用及其成瘤过程中机制的探讨
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摘要
随着电离辐射在医学、军事及核能开发等领域中的应用越来越广泛,人们对电离辐射危害的研究也不断增加。机体接受一定剂量的辐射可出现放射性损伤,包括氧化应激、造血系统功能异常、免疫功能障碍以及基因突变等,最终可能发生肿瘤。骨髓和胸腺是机体主要的中枢免疫器官,也是对辐射敏感的组织。因此,促进免疫器官辐射损伤的修复,是治疗放射病感染并发症、提高其救治水平的重要内容之一。目前,国内外对辐射损伤后骨髓功能恢复的治疗方法研究有了长足的进展,尤其是造血干细胞移植的应用。机体接受大剂量或全身照射时可发生多组织脏器损伤,造血干细胞移植不可能修复所有损伤,可能对辐射致死性骨髓损伤有一定效果,而对其他器官致死性损伤效果不佳。
骨髓间充质干细胞(mesenchymal stem cells, MSCs)是成体干细胞之一,许多动物实验表明,MSCs对放射性肠、肺脏、肾脏和脊髓等损伤有促进修复的作用。MSCs不仅可以向射线损伤的组织器官迁移,参与辐射损伤的修复,而且当机体各组织、器官均有损伤时,MSCs优先聚集在增生活跃、对射线最敏感的器官。
本文阐述了MSCs对胸腺辐射凋亡的作用,并探讨其在辐射诱发胸腺肿瘤过程中的机制,即同种异体MSCs可迁徙、定居到辐射损伤的胸腺组织内,参与细胞的再生,调控胸腺细胞周期进程,通过抑制p53和上调survivin和VEFG mRNA的表达，降低胸腺细胞的凋亡,从而促进胸腺组织的修复,并通过调控Wnt信号通路途径的关键调控因子β-catenin及下游靶基因c-myc与cyclin D1降低胸腺瘤的发生。本研究为辐射免疫损伤的治疗带来了新的希望,为MSCs在辐射损伤临床上的应用和进一步研究MSCs与肿瘤的关系提供了实验证据。
With the usage of ionizing radiation widely in medical, military and nuclear energy development fields, the study of ionizing radiation hazards for human body is increasing. When the human body is irradiated with a certain dose, the effect of radiation damage in it may develop, even malignant tumor or death. However, ionizing radiation can also kill tumor cells to treat the disease. In order to make better use of ionizing radiation, the radiation damage treated with the radiotherapy in combination with bone mesenchymal stem cells (MSCs) has become a hot spot on the study in the field of radiation medicin.
Bone marrow and thymus are not only the central immune organs, but also the sensitive tissues to ionizing radiation. Promoting the repair of immune organ damage is an important part of treating the infectious complications and improving the treatment effect on radiation sickness. At present, the treatment methods on functional recovery of bone marrow after radiation injury have made great progress, particularly the application of hematopoietic cytokines and hematopoietic stem cell transplantation. Cytokines can make the long-term survival of patients receiving 7-8 Gy irradiation. The multiple organ and tissue injuries can occur when irradiated with a large dose or whole body. The transplantation of hematopoietic stem cells may have some curative effect for the fatal injury of bone marrow cases without other organs.
MSCs are adult stem cells in the bone marrow. MSCs can home to the injury environment, which are amplified and participate in tissue repair or regeneration reaction in physiological or pathological conditions. Some animal experiments have showed that MSCs can promote the repair on the radiation damage organs, such as the radiation damages of intestinal, lung, renal, spinal cord and so on. MSCs not only migrate and involve in the repair of radiation damage, but also gather to the proliferation activity organ sensitized to ionizing radiation when the multiple tissues and organs are injured by irradiation. After the labeled MSCs united haploidentical bone marrow cells transplant to the 8-Gy irradiated mice. The labeled MSCs early appeared in bone marrow, thymus and small intestine cells, which largely amplified 15 d after transplantation. and further increased and changed structurally 30 d later. Based on the homing characteristics of MSCs to injury and the above-mentioned research results, it is feasible that MSCs are used in the repair on the thymus apoptosis by irradiation.
In this study, MSCs were separated and cultured in vitro with cell culture technology, and injected into the classic radiation animal model reported by Kaplan to investigate the repair effect of MSCs on the thymus. The mechanism of MSCs on thymic lymphoma formation and development induced by irradiation will be elucidated by observing the mRNA and protein expressions ofβ-catenin. a key regulator factor, and its downstream target genes of c-myc and cyclin D1 in Wnt signaling pathway. The results in this study will provide an important experimental basis for the application of MSCs in the radiation damage and the relationship between MSCs and tumor.
1. Isolation, culture and identification of MSCs
The bone marrow in humerus and femur of C57BL/6 neonatal mice was collected and MSCs was separated and purified with bone marrow all-adherent culture method. The MSCs morphology was observed and recorded through inverted phase contrast microscope. The MSCs growth characteristics was determined by MTT. The cell cycle progression and surface markers of MSCs were detected through flow cytometry. The osteoblast-like and fat-like cells were induced in vitro, and their differentiation results were identified with alkaline phosphatase and oil red O stainings. The results showed that the purified, amplified and stabilized MSCs were gotten with all-adherent culture method after isolated from the bone marrow of mice. The morphology of the purified stable passage MSCs was homogeneous and similar with fibroblast-like cells. The MSCs at 1 d after inoculation was in the incubation period after MSCs was inoculated, in the logarithmic growth phase at 2-5 d, and the divided cells entered in the platform phase 5 d later. The shape of growth curvein the MSCs was S type.69.1% MSCs were in the G0/G1 phase in the cell cycle. These results suggeste that MSCs are quiescent with a high proliferation and differentiation potential. MSCs did not express CD34 which is the surface marker of hematopoietic stem cells. The osteoblast-like differentiated from MSCs showed the positive alkaline phosphatase staining the and fat-like cells did the positive oil red O staining in vitro. These confirmed that the cells derived from the bone marrow were MSCs.
2. Mouse thymus damaged by ionizing radiation
The mouse model of thymus injury induced by irradiation was made according to the Kaplan' method. C57BL/6 mice were irradiated with the fractionation of X rays (1.75 Gy per time,1 time per week for consecutive four times, total doses of 7 Gy). The characteristics of the thymus structure was observated by histopathology at different time points, as compared with that in the normal mice. The structure of cortex and medulla in thymus was unclear, and the degeneration and necrosis of lymphocyte were seen. The regeneration and proliferation of lymphocytes in thymus occurred 60 d after irradiation,and the thymus size was similar with the normal control. The pre-cancerous changes were seen in the thymus 90 d later. While the thymus volume of mice with tumor increased, its capsule was damaged, the lymphoid.tumor cells were diffuse disposition, the tumor cells invaded into the fat cells 180 d later. The animal model of thymic injury and lymphoma induced by cumulative irradiation were established.
3. Effect of MSCs on thymus apoptosis by radiation
The allogeneic MSCs labeled with DAPI were transplanted into the model mice through the tail vein. The thymus tissues were taken out 1,5 and 10 d after MSCs were transplanted and made into frozen sections. The migration and settlement of MSCs were observed through confocal microscope. The cell cycle progression and apoptosis rate were detected by flow cytometry. The repair of MSCs on thymus damage was observated with histopathology. The occurrence of MSCs was observed in the thymus 1 d after the allogeneic MSCs were transplanted into the irradiated mice, the diffusion of them began 5 d later. The MSCs widely dispersed 10 d later, which can regulate the cell cycle progression of thymocytes, relieve the arrest of G0/G1 and G2/M phases induced by ionizing radiation, increase the percentage of S phase, reduce thymocyte apoptosis, and promote the repair of thymus damage. The thymus cortices proliferated highly, and its medulla reduced and the newborn lymphoid tissue in it can be seen 30 d after transplantation with MSCs. The thymus structure tended to the normal control 60 d later. MSCs can reduce the incidence of thymoma. In order to investigate the repair effect of MSCs on thymus damage, the expressions of p53, survivin, and VEGF mRNA were detected by RT-PCR in the thymus tissues of mice 30,60 and 90 d after transplantation with MSCs. The results showed that the expression of p53 mRNA increased significantly, while the expression of survivin mRNA reduced significantly 30 and 60 d after the mice were irradiated. After transplantation with MSCs. the expression of p53 mRNA was lower, while the expression of survivin mRNA was higher; the expression of VEGF mRNA was lower, but MSCs can promote its expression. With the the time prolongation of tissue repair, the expression of VEGF mRNA decreased gradually. These results indicate that MSCs can reduce the apoptosis of thymocytes by inhibiting p53 mRNA expressions and increasing surviving mRNA expressions, and promote vascular regeneration by increasing the expression of VEFG mRNA, and participate in the repair of radiation damage in the thymus.
4. Role of MSCs in course of thymoma induced by irradiation
After the mice transplanted with MSCs were irradiated, they were killed and the thymus of them were removed out 90 and 180 d. The expressions ofβ-catenin. c-myc and cyclin D1 mRNA were detected by RT-PCR and their protein expression positions in the thymus tissues were detected by immunohistochemistry. The results showed that the expressions ofβ-catenin, c-myc and cyclin D1 mRNA were detected in the proliferation and precancerous thymus tissues of irradiated mice. With the time prolongation after irradiation, the expressions of these genes gradually increased, and these protein expressions in the thymus cells also increased significantly. There was also significant correlation between the abnormal positive protein expression of P-catenin and the protein overexpressions of c-myc and cyclin D1. After transplantation with MSCs, the expressions ofβ-catenin, c-myc and cyclin D1 mRNA were lower and the protein positive expressions in the thymus cells is also lower than those in the unformed tumor and lymphoma tissues after irradiation. There was also significant correlation between the abnormal protein positive expression of P-catenin and the protein overexpression of c-myc, but not betweenβ-catenin and cyclin D1. These results indicate that the wnt signaling pathway involved in the occurrence of thymoma induced by irradiation, and MSCs could reduce the incidence of thymoma by regulating the key regulatory factorβ-catenin in this pathway and downstream target genes of c-myc and cyclin D1.
In one word, whole-body X-ray irradiation may cause the injury changes in the thymus tissue and induce lymphoma. The allogeneic MSCs can migrate and settle into the thymus. involve in the cell regeneration, regulate the cell cycle progression, decrease the apoptosis of thymocytes, promote the dameged thymus tissue repair, and reduce the incidence of thymoma by regulating the key regulatory factorβ-catenin in wnt signaling pathway and downstream target genes of c-myc and cyclin D1. The results in this study would bring a new hope for the treatment of immune injury from irradiation, provide the experimental evidence for the MSCs in the clinical application on radiation damage repair, and further study on the relationship between MSCs and tumors.
骨髓间充质干细胞(mesenchymal stem cells, MSCs)是成体干细胞之一,许多动物实验表明,MSCs对放射性肠、肺脏、肾脏和脊髓等损伤有促进修复的作用。MSCs不仅可以向射线损伤的组织器官迁移,参与辐射损伤的修复,而且当机体各组织、器官均有损伤时,MSCs优先聚集在增生活跃、对射线最敏感的器官。
本文阐述了MSCs对胸腺辐射凋亡的作用,并探讨其在辐射诱发胸腺肿瘤过程中的机制,即同种异体MSCs可迁徙、定居到辐射损伤的胸腺组织内,参与细胞的再生,调控胸腺细胞周期进程,通过抑制p53和上调survivin和VEFG mRNA的表达，降低胸腺细胞的凋亡,从而促进胸腺组织的修复,并通过调控Wnt信号通路途径的关键调控因子β-catenin及下游靶基因c-myc与cyclin D1降低胸腺瘤的发生。本研究为辐射免疫损伤的治疗带来了新的希望,为MSCs在辐射损伤临床上的应用和进一步研究MSCs与肿瘤的关系提供了实验证据。
With the usage of ionizing radiation widely in medical, military and nuclear energy development fields, the study of ionizing radiation hazards for human body is increasing. When the human body is irradiated with a certain dose, the effect of radiation damage in it may develop, even malignant tumor or death. However, ionizing radiation can also kill tumor cells to treat the disease. In order to make better use of ionizing radiation, the radiation damage treated with the radiotherapy in combination with bone mesenchymal stem cells (MSCs) has become a hot spot on the study in the field of radiation medicin.
Bone marrow and thymus are not only the central immune organs, but also the sensitive tissues to ionizing radiation. Promoting the repair of immune organ damage is an important part of treating the infectious complications and improving the treatment effect on radiation sickness. At present, the treatment methods on functional recovery of bone marrow after radiation injury have made great progress, particularly the application of hematopoietic cytokines and hematopoietic stem cell transplantation. Cytokines can make the long-term survival of patients receiving 7-8 Gy irradiation. The multiple organ and tissue injuries can occur when irradiated with a large dose or whole body. The transplantation of hematopoietic stem cells may have some curative effect for the fatal injury of bone marrow cases without other organs.
MSCs are adult stem cells in the bone marrow. MSCs can home to the injury environment, which are amplified and participate in tissue repair or regeneration reaction in physiological or pathological conditions. Some animal experiments have showed that MSCs can promote the repair on the radiation damage organs, such as the radiation damages of intestinal, lung, renal, spinal cord and so on. MSCs not only migrate and involve in the repair of radiation damage, but also gather to the proliferation activity organ sensitized to ionizing radiation when the multiple tissues and organs are injured by irradiation. After the labeled MSCs united haploidentical bone marrow cells transplant to the 8-Gy irradiated mice. The labeled MSCs early appeared in bone marrow, thymus and small intestine cells, which largely amplified 15 d after transplantation. and further increased and changed structurally 30 d later. Based on the homing characteristics of MSCs to injury and the above-mentioned research results, it is feasible that MSCs are used in the repair on the thymus apoptosis by irradiation.
In this study, MSCs were separated and cultured in vitro with cell culture technology, and injected into the classic radiation animal model reported by Kaplan to investigate the repair effect of MSCs on the thymus. The mechanism of MSCs on thymic lymphoma formation and development induced by irradiation will be elucidated by observing the mRNA and protein expressions ofβ-catenin. a key regulator factor, and its downstream target genes of c-myc and cyclin D1 in Wnt signaling pathway. The results in this study will provide an important experimental basis for the application of MSCs in the radiation damage and the relationship between MSCs and tumor.
1. Isolation, culture and identification of MSCs
The bone marrow in humerus and femur of C57BL/6 neonatal mice was collected and MSCs was separated and purified with bone marrow all-adherent culture method. The MSCs morphology was observed and recorded through inverted phase contrast microscope. The MSCs growth characteristics was determined by MTT. The cell cycle progression and surface markers of MSCs were detected through flow cytometry. The osteoblast-like and fat-like cells were induced in vitro, and their differentiation results were identified with alkaline phosphatase and oil red O stainings. The results showed that the purified, amplified and stabilized MSCs were gotten with all-adherent culture method after isolated from the bone marrow of mice. The morphology of the purified stable passage MSCs was homogeneous and similar with fibroblast-like cells. The MSCs at 1 d after inoculation was in the incubation period after MSCs was inoculated, in the logarithmic growth phase at 2-5 d, and the divided cells entered in the platform phase 5 d later. The shape of growth curvein the MSCs was S type.69.1% MSCs were in the G0/G1 phase in the cell cycle. These results suggeste that MSCs are quiescent with a high proliferation and differentiation potential. MSCs did not express CD34 which is the surface marker of hematopoietic stem cells. The osteoblast-like differentiated from MSCs showed the positive alkaline phosphatase staining the and fat-like cells did the positive oil red O staining in vitro. These confirmed that the cells derived from the bone marrow were MSCs.
2. Mouse thymus damaged by ionizing radiation
The mouse model of thymus injury induced by irradiation was made according to the Kaplan' method. C57BL/6 mice were irradiated with the fractionation of X rays (1.75 Gy per time,1 time per week for consecutive four times, total doses of 7 Gy). The characteristics of the thymus structure was observated by histopathology at different time points, as compared with that in the normal mice. The structure of cortex and medulla in thymus was unclear, and the degeneration and necrosis of lymphocyte were seen. The regeneration and proliferation of lymphocytes in thymus occurred 60 d after irradiation,and the thymus size was similar with the normal control. The pre-cancerous changes were seen in the thymus 90 d later. While the thymus volume of mice with tumor increased, its capsule was damaged, the lymphoid.tumor cells were diffuse disposition, the tumor cells invaded into the fat cells 180 d later. The animal model of thymic injury and lymphoma induced by cumulative irradiation were established.
3. Effect of MSCs on thymus apoptosis by radiation
The allogeneic MSCs labeled with DAPI were transplanted into the model mice through the tail vein. The thymus tissues were taken out 1,5 and 10 d after MSCs were transplanted and made into frozen sections. The migration and settlement of MSCs were observed through confocal microscope. The cell cycle progression and apoptosis rate were detected by flow cytometry. The repair of MSCs on thymus damage was observated with histopathology. The occurrence of MSCs was observed in the thymus 1 d after the allogeneic MSCs were transplanted into the irradiated mice, the diffusion of them began 5 d later. The MSCs widely dispersed 10 d later, which can regulate the cell cycle progression of thymocytes, relieve the arrest of G0/G1 and G2/M phases induced by ionizing radiation, increase the percentage of S phase, reduce thymocyte apoptosis, and promote the repair of thymus damage. The thymus cortices proliferated highly, and its medulla reduced and the newborn lymphoid tissue in it can be seen 30 d after transplantation with MSCs. The thymus structure tended to the normal control 60 d later. MSCs can reduce the incidence of thymoma. In order to investigate the repair effect of MSCs on thymus damage, the expressions of p53, survivin, and VEGF mRNA were detected by RT-PCR in the thymus tissues of mice 30,60 and 90 d after transplantation with MSCs. The results showed that the expression of p53 mRNA increased significantly, while the expression of survivin mRNA reduced significantly 30 and 60 d after the mice were irradiated. After transplantation with MSCs. the expression of p53 mRNA was lower, while the expression of survivin mRNA was higher; the expression of VEGF mRNA was lower, but MSCs can promote its expression. With the the time prolongation of tissue repair, the expression of VEGF mRNA decreased gradually. These results indicate that MSCs can reduce the apoptosis of thymocytes by inhibiting p53 mRNA expressions and increasing surviving mRNA expressions, and promote vascular regeneration by increasing the expression of VEFG mRNA, and participate in the repair of radiation damage in the thymus.
4. Role of MSCs in course of thymoma induced by irradiation
After the mice transplanted with MSCs were irradiated, they were killed and the thymus of them were removed out 90 and 180 d. The expressions ofβ-catenin. c-myc and cyclin D1 mRNA were detected by RT-PCR and their protein expression positions in the thymus tissues were detected by immunohistochemistry. The results showed that the expressions ofβ-catenin, c-myc and cyclin D1 mRNA were detected in the proliferation and precancerous thymus tissues of irradiated mice. With the time prolongation after irradiation, the expressions of these genes gradually increased, and these protein expressions in the thymus cells also increased significantly. There was also significant correlation between the abnormal positive protein expression of P-catenin and the protein overexpressions of c-myc and cyclin D1. After transplantation with MSCs, the expressions ofβ-catenin, c-myc and cyclin D1 mRNA were lower and the protein positive expressions in the thymus cells is also lower than those in the unformed tumor and lymphoma tissues after irradiation. There was also significant correlation between the abnormal protein positive expression of P-catenin and the protein overexpression of c-myc, but not betweenβ-catenin and cyclin D1. These results indicate that the wnt signaling pathway involved in the occurrence of thymoma induced by irradiation, and MSCs could reduce the incidence of thymoma by regulating the key regulatory factorβ-catenin in this pathway and downstream target genes of c-myc and cyclin D1.
In one word, whole-body X-ray irradiation may cause the injury changes in the thymus tissue and induce lymphoma. The allogeneic MSCs can migrate and settle into the thymus. involve in the cell regeneration, regulate the cell cycle progression, decrease the apoptosis of thymocytes, promote the dameged thymus tissue repair, and reduce the incidence of thymoma by regulating the key regulatory factorβ-catenin in wnt signaling pathway and downstream target genes of c-myc and cyclin D1. The results in this study would bring a new hope for the treatment of immune injury from irradiation, provide the experimental evidence for the MSCs in the clinical application on radiation damage repair, and further study on the relationship between MSCs and tumors.
引文
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