骨形态发生蛋白激活自身肌肉间质细胞拯救骨髓衰竭

Activation of Auto-Mesenchymal Stem Cells of Skeletal Muscle by Bone Morphogenetic Protein for Rescuing Bone Marrow Failure

目的探讨骨形态发生蛋白(BMP)激活自身肌肉间质细胞以拯救骨髓造血衰竭的作用。方法采用5-氟脲嘧啶与白消安合用诱导大鼠致死性再生障碍性贫血模型,于诱导再障前3d肌肉内植入重组人-BMP-2(rh-BMP-2),并以肌肉内植入琼脂为对照。观察血象、病理形态等变化以及两组再障大鼠的死亡率。同时,给正常小鼠大腿肌肉内植入rh-BMP-2,动态观察植入后局部的形态变化、形成骨及骨髓的形态特点,脾集落形成单位以及基质细胞干细胞生长因子(SCF)的表达。结果小鼠在BMP肌肉内植入1周内,在BMP周围有大量间质细胞增殖,随后形成骨及骨髓,其骨髓基质细胞的SCF表达明显高于自体骨髓;BMP植入组的再障大鼠,不仅血象与对照相比有明显改善,而且死亡率也明显下降,有56.3%大鼠存活超过3个月,其血象完全恢复正常,骨髓和脾脏的组织形态学改变也恢复正常。对照大鼠除1只存活超过3个月外(占4.3%),其余均死于急性再生障碍性贫血。结论BMP肌肉内植入可拯救骨髓造血衰竭,其机制可能与BMP诱导成年自体肌肉内存在的干细胞向造血分化有关;本研究结果为应用成体自身干细胞进行细胞治疗提供了新的途径。

Objective To explore the effect of bone morphogenetic protein(BMP)to activate mesenchymal stem cells of skeletal muscle for rescuing bone marrow failure.Method s The study was performed on lethal rat acute aplastic anemia model induced by combined5-fluorouracil(5-FU)and busulfan.The rh-BMP -2was implanted into the thigh muscle of the rats at3days before aplastic anemia was induced.In the control group the rats were implanted with agar into the thigh muscle.The blood picture,pathologic changes and the mortality in two groups were observed.At the same time,rh-BMP -2were implanted into the thigh muscle of normal Kun-min mice for dynamic control observa tion of the implantation local morphological changes,colony forming units-spleen (CFU-S)and stem cell growth factor(SCF)expression of the stroma cells of ectopic ossicles induced by BMP.Results At 7days after BMP implantation in the mice the mesenchymal cells around BMP in muscle proliferated,and appeared in bone marrow to form an ectopic ossicles.The SCF expression of stroma cells in ectopic ossicles were higher than that of self-bone marrow.56.3%of BMP -treated aplastic rats were survived over3months and its hematopoiesis was completely reconstituted and the histo-morphological picture of the spleen and bone marrow were recovered to normal.But in the control group only one of23rats was survived,the remainder died of hematopoietic failure.Conclusions BMP -implantation into the skeletal muscle could rescue the bone marrow hematopoietic failure.The mechanism might be related to the BMP activated auto-mesenchymal cells of skeletal muscles to direct hematopietic cell differentiation.In our hands it might create a new pathway for utilization of auto-muscle derived mesenchymal cells to reconstitute hematopoiesis.