小鼠多潜能成体干细胞生物学特性及向树突状细胞分化的研究
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摘要
越来越多的研究发现成体干细胞具有跨系甚至跨胚层分化的特性，即成体干细胞具有可塑性，而对于可塑性的原因和机制，目前更多的学者认为在成体组织中可能存在着原始的多潜能干细胞，我们命名为胚胎后亚全能干细胞。对于亚全能干细胞的分离与鉴定不论对于基础研究还是临床应用都具有非常重要的意义和不可低估的价值。
本文的第一部分，是从小鼠胚胎成纤维细胞中成功分离出一群原始的Sca-1~((+))CD117~((-))Lin~((-))多潜能干细胞，对于其生物学特性进行了全面而细致的研究。发现该细胞群表达胚胎干细胞相关的转录因子，具有朝三胚层细胞分化的能力，并且拥有免疫调节性能。在体实验表明该细胞群能够延长异基因来源的皮肤移植物的存活时间，皮肤烧伤实验证明其能够显著促进皮肤损伤的愈合。我们的实验为胚胎后亚全能干细胞在体内的存在提供了进一步的支持证据，丰富了成体干细胞可塑性的基本理论。第二部分目的是考察Sca-1~((+))CD117~((-))Lin~((-))多潜能干细胞是否能够在体外朝造血细胞分化。使用合适的诱导条件，我们诱导Sca-1~((+))CD117~((-))Lin~((-))分化为具有免疫调节功能的树突状细胞，对于分化而来的树突状细胞我们详细的考察了其生物学特性。进一步发现，这些树突状细胞通过Notch-Jagged信号通路的调节而发挥免疫抑制的效应。提示这类诱导的树突状细胞有可能在临床上具有治疗免疫相关性疾病的前景。
Most of the adult stem cells not only generate those mature cell types corresponding to their tissue of origin, but also cross tissue (or germ layer) boundaries to generate cell types of different lineages, which was named as adult stem cell plasticity, however, the explanations of adult stem cell plasticity remain a point of discussion and controversy. One well accepted possible mechanism for observation of adult stem cell plasticity relates to the action of rare pluripotent stem cells (PSCs) present in the test cell population.
In the first part, we have succeeded in isolating Sca-l~+CD117~-Lin~- primitive pluripotent stem cells from the mouse embryonic fibroblast populaiton. This cell population possesses the main characteristics of primitive pluripotent stem cells, including expression of embryonic stem cells (ESCs) marker, ability of giving rise to multiple types of three germ layers and potential of immunoregulation. In vivo studies indicated that the cell population could prolong the survival of allogeneic skin grafts, and strikingly promote the skin burn would healing by differentiating into multiple types of cells in the dermal and epidermal tissues. Our study will help us better understand the properties of plasticity and may greatly contribute to the use of stem cells as a target for cell transplantation and gene therapy.
The second part indicated that the Sca-1~+CD117~-Lin~- pluripotent stem cells could be induced to differentiate into CD11b~(high) Ia~(low)CD11c~(low) dendritic cells (DCs) with strong regulatory functions capable of suppressing mixed lymphocyte reaction, allogeneic delayed type-hypersensitivity and rejection of allogeneic skin grafts. The immune regulatory functions of these dendritic cells were found to be mediated by Jagged-2. Our studies revealed that ESC-like pluripotent stem cells exist in freshly isolated mouse embryonic fibroblast population and they can differentiate into DCs with strong regulatory functions.
本文的第一部分，是从小鼠胚胎成纤维细胞中成功分离出一群原始的Sca-1~((+))CD117~((-))Lin~((-))多潜能干细胞，对于其生物学特性进行了全面而细致的研究。发现该细胞群表达胚胎干细胞相关的转录因子，具有朝三胚层细胞分化的能力，并且拥有免疫调节性能。在体实验表明该细胞群能够延长异基因来源的皮肤移植物的存活时间，皮肤烧伤实验证明其能够显著促进皮肤损伤的愈合。我们的实验为胚胎后亚全能干细胞在体内的存在提供了进一步的支持证据，丰富了成体干细胞可塑性的基本理论。第二部分目的是考察Sca-1~((+))CD117~((-))Lin~((-))多潜能干细胞是否能够在体外朝造血细胞分化。使用合适的诱导条件，我们诱导Sca-1~((+))CD117~((-))Lin~((-))分化为具有免疫调节功能的树突状细胞，对于分化而来的树突状细胞我们详细的考察了其生物学特性。进一步发现，这些树突状细胞通过Notch-Jagged信号通路的调节而发挥免疫抑制的效应。提示这类诱导的树突状细胞有可能在临床上具有治疗免疫相关性疾病的前景。
Most of the adult stem cells not only generate those mature cell types corresponding to their tissue of origin, but also cross tissue (or germ layer) boundaries to generate cell types of different lineages, which was named as adult stem cell plasticity, however, the explanations of adult stem cell plasticity remain a point of discussion and controversy. One well accepted possible mechanism for observation of adult stem cell plasticity relates to the action of rare pluripotent stem cells (PSCs) present in the test cell population.
In the first part, we have succeeded in isolating Sca-l~+CD117~-Lin~- primitive pluripotent stem cells from the mouse embryonic fibroblast populaiton. This cell population possesses the main characteristics of primitive pluripotent stem cells, including expression of embryonic stem cells (ESCs) marker, ability of giving rise to multiple types of three germ layers and potential of immunoregulation. In vivo studies indicated that the cell population could prolong the survival of allogeneic skin grafts, and strikingly promote the skin burn would healing by differentiating into multiple types of cells in the dermal and epidermal tissues. Our study will help us better understand the properties of plasticity and may greatly contribute to the use of stem cells as a target for cell transplantation and gene therapy.
The second part indicated that the Sca-1~+CD117~-Lin~- pluripotent stem cells could be induced to differentiate into CD11b~(high) Ia~(low)CD11c~(low) dendritic cells (DCs) with strong regulatory functions capable of suppressing mixed lymphocyte reaction, allogeneic delayed type-hypersensitivity and rejection of allogeneic skin grafts. The immune regulatory functions of these dendritic cells were found to be mediated by Jagged-2. Our studies revealed that ESC-like pluripotent stem cells exist in freshly isolated mouse embryonic fibroblast population and they can differentiate into DCs with strong regulatory functions.
引文
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