CD43表达与造血干细胞发育的相关性研究
发布时间：2018-07-16 15:35
【摘要】：在胚胎的发育过程中,第一个造血干细胞(hematopoietic stem cells, HSC)产生于胚内的主动脉-性腺-中肾区(aorta-gonads-mesonephros region,AGM区),稍后出现在胎盘和卵黄囊,而后迁移到胎肝。出生后骨髓代替胎肝成为造血活动的主要场所。这些不同的造血微环境为HSC的产生、成熟、扩增和分化提供合适的调控信号。由于体外的培养条件不足以模拟体内复杂的微环境,HSC在体外容易失去“干性”。组织培养(tissue culture)的方法可保留组织内部三维的、更接近生理状态的微环境,在体外可显著促进HSC的成熟和增殖。在小鼠体节期胚胎,HSC在不同的时间和位点发生。在发育早期(胚胎期10.5-11.5天),HSC数目极少(约1-3个/胚胎),且无特异性的表面标志,这为探讨HSC的发育调控机制增加了难度。因此,为了分离和纯化HSC、明确HSC的具体定位、揭示其发育规律,发现和鉴定新的造血和/或HSC的特异性标记显得尤为重要。 本研究的第一部分,我们通过建立特殊的组织培养方法,探讨小鼠胚胎AGM区的造血发育规律。选取小鼠E10.5-E11胚胎的AGM区作为实验对象,建立气液交界的组织培养体系,孵育2天后作如下三类分析:应用集落形成实验在体外观察髓系祖细胞的数量,应用脾结节形成(colony-forming unit of spleen, CFU-S)实验在体内检测髓系祖细胞的变化,利用移植(长期重建)实验考察HSC的发育。结果表明:组织培养后,平均每个E10.5 AGM区的细胞可形成104±18个髓系集落;每个E10.5 AGM区的细胞在致死剂量照射的成年小鼠脾脏中可形成10.8±3.5个CFU-S。更重要的是,经组织培养的E10.5-E11.5 AGM区能高比例(85.7%)、高嵌合(51.12%±21.17%)、长期(4个月)重建致死剂量照射的成年小鼠的造血系统,在受体的外周血、骨髓、脾脏、胸腺中均能检测到供体来源的淋系或髓系细胞的嵌合。上述数据与经典文献结果相似,证实:体外组织培养确能促进小鼠AGM区HSC的成熟和扩增,是研究胚胎造血发育规律的有效方法。 本研究的第二部分,借助于建立的组织培养和移植体系,我们集中研究CD43在不同发育时间和位点的HSC的表达特点。CD43,亦称leukosialin或sialophorin,与CD34、Endomucin等分子都属于内皮唾液黏蛋白质家族成员,具有完整的细胞膜表面黏蛋白。我们的研究立题主要基于如下几点:既往研究表明CD43在人和小鼠的骨髓HSC高表达;人胚胎干细胞和诱导多能干细胞来源的造血祖细胞表达CD43;其表达于人胚胎背主动脉腹侧造血簇(富集造血干祖细胞的特殊细胞群)。此外,CD43与小鼠胚胎发育过程中重要的HSC表面标志CD34在结构上相似,两者标志意义的异同亦是我们感兴趣的问题。 为明确CD43在AGM区HSC中的表达,我们将E10.5、E11.5、E12.5 AGM区消化成单细胞悬液,利用免疫磁珠分选,获得CD43+细胞和CD43-细胞,分别按照1-2个胚胎量移植入60Co致死剂量(9 Gy)照射的成年受体小鼠。移植后4个月对外周血进行检测,计算(GFP+CD45+)/CD45+的比值得到嵌合率,≥10%则视为重建。结果发现E10.5、E11.5、E12.5 AGM区CD43+细胞的重建比例分别为2/15、6/12、4/4。相反,所有的CD43-细胞移植受体均未发现重建(n=26)。受体的外周血、骨髓、脾脏、胸腺中含有供体来源的相当比例的髓系、B淋巴细胞、T淋巴细胞,表明AGM区CD43+细胞具有多系分化潜能。同时,通过二次移植实验,证实AGM区CD43+细胞具有自我更新能力。既往研究表明AGM区的HSC存在于c-Kit+CD34+细胞中。进一步的流式分析发现CD43在E11.5AGM的该群细胞中的表达比例为16.2%-22.3%,提示其具有潜在的富集意义。上述数据表明:小鼠胚胎AGM区的HSC均分布在CD43+亚群。 既往研究发现:E11.5 AGM区经体外组织培养后,HSC的免疫表型发生变化,从CD34+转变成CD34-,与成体骨髓HSC相同。为明确CD43是否有类似特点,我们将AGM区(E10.5-E11.5)进行2天的组织培养,磁珠分选获得CD43+细胞和CD43-细胞,而后移植入致死剂量照射的受体小鼠。结果发现:E10.5、E11.5 AGM区CD43+细胞的重建比例分别为4/4和6/6,而CD43-细胞均不能重建(n=7)。重建受体的外周血、骨髓、脾脏、胸腺中含有供体来源的相当比例的髓系或淋系细胞,表明经组织培养的AGM区CD43+细胞仍然具有多系分化潜能。上述数据表明:组织培养能促进AGM区CD43+HSC的扩增;与CD34不同,在HSC的体外成熟和增殖过程中,CD43持续表达。 近年来,多项研究表明:与AGM区和卵黄囊相似,胎盘也是HSC发育的另一重要位点。为进一步明确CD43在胎盘和卵黄囊来源的HSC中的表达,我们分别将E11.5胎盘和卵黄囊的CD43+细胞和CD43-细胞移植入致死剂量照射的受体小鼠。结果发现胎盘CD43+细胞重建比例为7/7,卵黄囊为5/8,而CD43-细胞均重建失败(n=13)。此外,E11.5胎盘和卵黄囊的CD43+细胞亦具有多系分化潜能。既往研究表明胎盘和卵黄囊中的HSC存在于c-Kit+CD34+细胞中,我们的流式分析发现E11.5胎盘和卵黄囊的该群双阳性细胞中分别有21.2%-33.7%和14.9%-24.0%表达CD43,提示可通过CD43进一步富集上述组织中的HSC。以上数据表明胎盘和卵黄囊中的HSC均表达CD43。 胚胎造血时期,AGM区、胎盘、卵黄囊来源的HSC可通过血液循环定居于胎肝,后者成为最重要的HSC扩增位点。为了明确胎肝中的HSC是否表达CD43,我们将E12.5胎肝的CD43+细胞和CD43-细胞移植入致死剂量照射的受体小鼠。结果发现只有胎肝CD43+细胞能重建成体造血(重建比例为5/5),且具有造血多系分化潜能。之前研究表明CD45在E11.5以后开始在HSC上表达。为进一步确定CD43在不同发育阶段胎肝HSC中的表达,我们利用CD43和CD45抗体标记E13.5和E16.5的胎肝细胞,经流式分选获得CD45+CD43high、CD45+CD43mid和CD45+CD43-三群细胞。将其移植后发现仅CD45+CD43high细胞能重建成体造血(E13.5和E16.5的重建比例分别为3/3和6/7),该现象与成体骨髓HSC集中于CD43high亚群相似。与之吻合的是,流式分析发现:富集胎肝HSC的亚群,即Lin-Sca-1+c-Kit+细胞中,CD43的阳性比例95%。 总结:既往认为CD43是一个类似于CD45的造血标志,而本研究将其表达与早期的造血发生紧密的关联起来。作为一个新的胚胎造血发育时期的特异性标记,CD43的独特性表现为:持续表达于HSC发育的各个重要阶段(出现、成熟、扩增)、各个造血组织(AGM区、胎盘、卵黄囊、胎肝)。因此,CD43的标志作用为今后研究基因敲除小鼠的胚胎造血活动提供了一个灵敏的标识,其生理功能亦待进一步深入研究。
[Abstract]:In the development of embryo, the first hematopoietic stem cell (hematopoietic stem cells, HSC) is produced in the aorta sex gland and the middle kidney region (aorta-gonads-mesonephros region, AGM region) in the embryo, and later appears in the placenta and the yolk sac and then migrates to the fetal liver. The hematopoietic microenvironment is the production of HSC, mature, amplified and differentiated to provide appropriate regulatory signals. Because the culture conditions in vitro are not sufficient to simulate the complex microenvironment in the body, HSC is easy to lose the "dry" in vitro. The method of tissue culture (tissue culture) can retain the three-dimensional inner part of the tissue, which is closer to the physiological state, and in vitro It can significantly promote the maturation and proliferation of HSC. In mice, HSC occurs at different time and loci. In early development (10.5-11.5 days of embryo stage), the number of HSC is very few (about 1-3 / embryos), and there is no specific surface marker. This makes it difficult to explore the development and regulation mechanism of HSC. Therefore, to separate and purify HSC and clarify HSC It is particularly important to find out and identify new hematopoietic and / or HSC specific markers.
In the first part of this study, we explored the regulation of hematopoiesis in the AGM region of mouse embryos by establishing a special tissue culture method. The AGM area of E10.5-E11 embryos of mice was selected as the experimental object, and the tissue culture system of the boundary of gas and liquid was established. After 2 days of incubation, the following three types of analysis were made: using colony formation experiment to observe the medullary lineage in vitro The number of colony-forming unit of spleen (CFU-S) was used to detect the changes of myeloid progenitor cells in the body. The development of HSC was investigated by transplantation (long term reconstruction). The results showed that after tissue culture, the cells of each E10.5 AGM area could form 104 + 18 medullary colony, and the cells in each E10.5 AGM region were lethal. In the spleen of adult mice irradiated with dose, 10.8 + 3.5 CFU-S. are more important, and the hematopoietic system of adult mice with high proportion (85.7%), high chimerism (51.12% + 21.17%) and long-term (4 months) reconstruction of lethal dose in the tissue culture of the adult mice can be detected in the peripheral blood, bone marrow, spleen and thymus of the recipient. The above data are similar to those of classical literature. It is proved that tissue culture in vitro can promote the maturation and amplification of HSC in AGM region of mice, and is an effective method to study the rules of embryo hematopoiesis.
In the second part of this study, with the aid of the established tissue culture and transplantation system, we focus on the HSC expression of CD43 at different developmental time and loci.CD43, also known as leukosialin or sialophorin, and CD34, Endomucin and other molecules are members of the endothelial salivary mucin family, with a complete cell membrane surface mucin. The main points of our research are based on the following points: Previous studies have shown that CD43 is highly expressed in human and mouse bone marrow HSC; human embryonic stem cells and hematopoietic progenitors that induce pluripotent stem cells express CD43; they are expressed in the ventral hemopoietic cluster of the human embryonic dorsal aorta (a special cell group enriched with hematopoietic progenitor cells). In addition, CD43 and mouse embryos are also expressed. The important HSC surface marker CD34 is similar in structure. The similarities and differences between the two markers are also interesting issues.
To clarify the expression of CD43 in the AGM region HSC, we digested E10.5, E11.5 and E12.5 AGM into single cell suspension, and obtained CD43+ cells and CD43- cells by immunomagnetic beads, and transplanted into the adult receptor mice irradiated by 60Co lethal dose (9 Gy) according to 1-2 embryos, respectively. After 4 months of transplantation, the peripheral blood was detected and calculated (GFP+CD45+) The ratio of D45+ was found to be chimerism, and more than 10% was regarded as reconstruction. The results showed that the reconstruction ratio of CD43+ cells in E10.5, E11.5, E12.5 AGM region was 2/15,6/12,4/4., and all CD43- cell transplantation recipients were not found to reconstruct (n=26). The peripheral blood of the receptor, bone marrow, spleen, and chest gland contained a considerable proportion of myeloid, B lymphocytes, T lymphocyte, indicating that CD43+ cells in AGM region have multiple differentiation potential. At the same time, two transplanting experiments confirmed that CD43+ cells in AGM region have self-renewal ability. Previous studies showed that HSC in AGM region existed in c-Kit+CD34+ cells. Further flow analysis showed that the proportion of CD43 in this group of E11.5AGM was 16.2%-22.3%. These data indicate that HSC in AGM region of mouse embryos is distributed in CD43+ subsets.
Previous studies have found that the immunophenotype of the E11.5 AGM region changes after the culture in vitro, and the immunophenotype of HSC changes from CD34+ to CD34- and is the same as that of adult bone marrow HSC. In order to clarify whether there is a similar characteristic of CD43, we carry out AGM region (E10.5-E11.5) for 2 days of tissue culture, and obtain CD43+ cells and CD43- cells from magnetic beads, and then transplant to lethal dose illumination. The results showed that the reconstruction ratio of CD43+ cells in E10.5, E11.5 AGM region was 4/4 and 6/6 respectively, while CD43- cells were not rebuilt (n=7). The peripheral blood, bone marrow, spleen, and thymus contained a considerable proportion of myeloid or lymphoid cells in the rebuilt receptor, indicating that the tissue culture of AGM region CD43+ cells still had multiple lines. The above data indicate that tissue culture can promote the amplification of CD43+HSC in AGM region. Unlike CD34, CD43 is continuously expressed during HSC maturation and proliferation in vitro.
In recent years, many studies have shown that the placenta is another important site for the development of HSC, similar to the AGM region and the yolk sac. In order to further clarify the expression of CD43 in the HSC from the source of the placenta and the yolk sac, we transplanted the CD43+ and CD43- cells of the E11.5 placenta and the yolk sac into the receptor mice irradiated at the dead dose, and found the placental CD43. The reconstructive ratio of + cells was 7/7, the yolk sac was 5/8, and the CD43- cells were rebuilt (n=13). In addition, the CD43+ cells of the E11.5 placenta and the yolk sac also had multiple differentiation potential. Previous studies showed that the HSC in the placenta and the yolk sac was found in c-Kit+CD34+ cells. Our flow cytometry found the group of double positive cells in the E11.5 placenta and the yolk sac. 21.2%-33.7% and 14.9%-24.0% expressed CD43, respectively, suggesting that CD43 could be further enriched by CD43 in the above tissue, indicating that HSC in the placenta and yolk sac expressed CD43.
In the embryonic period of hematopoiesis, the AGM region, the placenta, and the yolk sac derived from the HSC can be settled in the fetal liver through the blood circulation, and the latter becomes the most important HSC amplification site. In order to determine whether the HSC in the fetal liver is CD43, we transplant CD43+ cells and CD43- cells from the E12.5 fetal liver to the lethal dose irradiated recipient mice. The result is that only the fetal liver CD43+ is fine. The cell can reconstruct the adult hematopoiesis (reconstructive ratio of 5/5) and have the potential of hematopoietic pluripotent differentiation. Previous studies showed that CD45 began to express on HSC after E11.5. To further determine the expression of CD43 in the HSC of fetal liver at different developmental stages, we use CD43 and CD45 antibodies to mark the fetal liver cells of E13.5 and E16.5 and obtain CD45+CD43hig by flow sorting. H, CD45+CD43mid and CD45+CD43- three cells. After transplantation, it was found that only CD45+CD43high cells could reconstruct adult hematopoiesis (the proportion of E13.5 and E16.5 reconstruction was 3/3 and 6/7). This phenomenon was similar to that of adult marrow HSC concentrated in the CD43high subgroup. In the case of CD43, the positive ratio of 95%.
Summary: CD43 was previously thought to be a hematopoiesis marker similar to CD45, and this study associated its expression closely with early hematopoiesis. As a specific marker for a new period of embryonic hematopoiesis, the uniqueness of CD43 is expressed continuously in all important stages of the development of HSC (emergence, maturation, amplification), and every hematopoiesis Tissue (AGM region, placenta, yolk sac, fetal liver). Therefore, the marker function of CD43 provides a sensitive marker for the future study of embryo hematopoiesis in gene knockout mice, and its physiological function should be further studied.
【学位授予单位】：中国人民解放军军事医学科学院
【学位级别】：硕士
【学位授予年份】：2011
【分类号】：R329
本文编号：2126836
[Abstract]:In the development of embryo, the first hematopoietic stem cell (hematopoietic stem cells, HSC) is produced in the aorta sex gland and the middle kidney region (aorta-gonads-mesonephros region, AGM region) in the embryo, and later appears in the placenta and the yolk sac and then migrates to the fetal liver. The hematopoietic microenvironment is the production of HSC, mature, amplified and differentiated to provide appropriate regulatory signals. Because the culture conditions in vitro are not sufficient to simulate the complex microenvironment in the body, HSC is easy to lose the "dry" in vitro. The method of tissue culture (tissue culture) can retain the three-dimensional inner part of the tissue, which is closer to the physiological state, and in vitro It can significantly promote the maturation and proliferation of HSC. In mice, HSC occurs at different time and loci. In early development (10.5-11.5 days of embryo stage), the number of HSC is very few (about 1-3 / embryos), and there is no specific surface marker. This makes it difficult to explore the development and regulation mechanism of HSC. Therefore, to separate and purify HSC and clarify HSC It is particularly important to find out and identify new hematopoietic and / or HSC specific markers.
In the first part of this study, we explored the regulation of hematopoiesis in the AGM region of mouse embryos by establishing a special tissue culture method. The AGM area of E10.5-E11 embryos of mice was selected as the experimental object, and the tissue culture system of the boundary of gas and liquid was established. After 2 days of incubation, the following three types of analysis were made: using colony formation experiment to observe the medullary lineage in vitro The number of colony-forming unit of spleen (CFU-S) was used to detect the changes of myeloid progenitor cells in the body. The development of HSC was investigated by transplantation (long term reconstruction). The results showed that after tissue culture, the cells of each E10.5 AGM area could form 104 + 18 medullary colony, and the cells in each E10.5 AGM region were lethal. In the spleen of adult mice irradiated with dose, 10.8 + 3.5 CFU-S. are more important, and the hematopoietic system of adult mice with high proportion (85.7%), high chimerism (51.12% + 21.17%) and long-term (4 months) reconstruction of lethal dose in the tissue culture of the adult mice can be detected in the peripheral blood, bone marrow, spleen and thymus of the recipient. The above data are similar to those of classical literature. It is proved that tissue culture in vitro can promote the maturation and amplification of HSC in AGM region of mice, and is an effective method to study the rules of embryo hematopoiesis.
In the second part of this study, with the aid of the established tissue culture and transplantation system, we focus on the HSC expression of CD43 at different developmental time and loci.CD43, also known as leukosialin or sialophorin, and CD34, Endomucin and other molecules are members of the endothelial salivary mucin family, with a complete cell membrane surface mucin. The main points of our research are based on the following points: Previous studies have shown that CD43 is highly expressed in human and mouse bone marrow HSC; human embryonic stem cells and hematopoietic progenitors that induce pluripotent stem cells express CD43; they are expressed in the ventral hemopoietic cluster of the human embryonic dorsal aorta (a special cell group enriched with hematopoietic progenitor cells). In addition, CD43 and mouse embryos are also expressed. The important HSC surface marker CD34 is similar in structure. The similarities and differences between the two markers are also interesting issues.
To clarify the expression of CD43 in the AGM region HSC, we digested E10.5, E11.5 and E12.5 AGM into single cell suspension, and obtained CD43+ cells and CD43- cells by immunomagnetic beads, and transplanted into the adult receptor mice irradiated by 60Co lethal dose (9 Gy) according to 1-2 embryos, respectively. After 4 months of transplantation, the peripheral blood was detected and calculated (GFP+CD45+) The ratio of D45+ was found to be chimerism, and more than 10% was regarded as reconstruction. The results showed that the reconstruction ratio of CD43+ cells in E10.5, E11.5, E12.5 AGM region was 2/15,6/12,4/4., and all CD43- cell transplantation recipients were not found to reconstruct (n=26). The peripheral blood of the receptor, bone marrow, spleen, and chest gland contained a considerable proportion of myeloid, B lymphocytes, T lymphocyte, indicating that CD43+ cells in AGM region have multiple differentiation potential. At the same time, two transplanting experiments confirmed that CD43+ cells in AGM region have self-renewal ability. Previous studies showed that HSC in AGM region existed in c-Kit+CD34+ cells. Further flow analysis showed that the proportion of CD43 in this group of E11.5AGM was 16.2%-22.3%. These data indicate that HSC in AGM region of mouse embryos is distributed in CD43+ subsets.
Previous studies have found that the immunophenotype of the E11.5 AGM region changes after the culture in vitro, and the immunophenotype of HSC changes from CD34+ to CD34- and is the same as that of adult bone marrow HSC. In order to clarify whether there is a similar characteristic of CD43, we carry out AGM region (E10.5-E11.5) for 2 days of tissue culture, and obtain CD43+ cells and CD43- cells from magnetic beads, and then transplant to lethal dose illumination. The results showed that the reconstruction ratio of CD43+ cells in E10.5, E11.5 AGM region was 4/4 and 6/6 respectively, while CD43- cells were not rebuilt (n=7). The peripheral blood, bone marrow, spleen, and thymus contained a considerable proportion of myeloid or lymphoid cells in the rebuilt receptor, indicating that the tissue culture of AGM region CD43+ cells still had multiple lines. The above data indicate that tissue culture can promote the amplification of CD43+HSC in AGM region. Unlike CD34, CD43 is continuously expressed during HSC maturation and proliferation in vitro.
In recent years, many studies have shown that the placenta is another important site for the development of HSC, similar to the AGM region and the yolk sac. In order to further clarify the expression of CD43 in the HSC from the source of the placenta and the yolk sac, we transplanted the CD43+ and CD43- cells of the E11.5 placenta and the yolk sac into the receptor mice irradiated at the dead dose, and found the placental CD43. The reconstructive ratio of + cells was 7/7, the yolk sac was 5/8, and the CD43- cells were rebuilt (n=13). In addition, the CD43+ cells of the E11.5 placenta and the yolk sac also had multiple differentiation potential. Previous studies showed that the HSC in the placenta and the yolk sac was found in c-Kit+CD34+ cells. Our flow cytometry found the group of double positive cells in the E11.5 placenta and the yolk sac. 21.2%-33.7% and 14.9%-24.0% expressed CD43, respectively, suggesting that CD43 could be further enriched by CD43 in the above tissue, indicating that HSC in the placenta and yolk sac expressed CD43.
In the embryonic period of hematopoiesis, the AGM region, the placenta, and the yolk sac derived from the HSC can be settled in the fetal liver through the blood circulation, and the latter becomes the most important HSC amplification site. In order to determine whether the HSC in the fetal liver is CD43, we transplant CD43+ cells and CD43- cells from the E12.5 fetal liver to the lethal dose irradiated recipient mice. The result is that only the fetal liver CD43+ is fine. The cell can reconstruct the adult hematopoiesis (reconstructive ratio of 5/5) and have the potential of hematopoietic pluripotent differentiation. Previous studies showed that CD45 began to express on HSC after E11.5. To further determine the expression of CD43 in the HSC of fetal liver at different developmental stages, we use CD43 and CD45 antibodies to mark the fetal liver cells of E13.5 and E16.5 and obtain CD45+CD43hig by flow sorting. H, CD45+CD43mid and CD45+CD43- three cells. After transplantation, it was found that only CD45+CD43high cells could reconstruct adult hematopoiesis (the proportion of E13.5 and E16.5 reconstruction was 3/3 and 6/7). This phenomenon was similar to that of adult marrow HSC concentrated in the CD43high subgroup. In the case of CD43, the positive ratio of 95%.
Summary: CD43 was previously thought to be a hematopoiesis marker similar to CD45, and this study associated its expression closely with early hematopoiesis. As a specific marker for a new period of embryonic hematopoiesis, the uniqueness of CD43 is expressed continuously in all important stages of the development of HSC (emergence, maturation, amplification), and every hematopoiesis Tissue (AGM region, placenta, yolk sac, fetal liver). Therefore, the marker function of CD43 provides a sensitive marker for the future study of embryo hematopoiesis in gene knockout mice, and its physiological function should be further studied.
【学位授予单位】：中国人民解放军军事医学科学院
【学位级别】：硕士
【学位授予年份】：2011
【分类号】：R329
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