人脐血基质细胞联合移植促进造血细胞归巢植入及支持造血重建的实验研究
发布时间：2018-09-06 06:49
【摘要】：造血微环境(hematopoietic inductive microenvironment,HIM)是支持和调节造血干/祖细胞(haemopoietic stem/progenitor cell,HSPC)生长发育的内环境,其结构和功能的完整统一是维系造血功能正常进行的重要环节。作为造血微环境的重要组成部分,基质细胞可能通过形成造血干细胞(hematopoietic stem cell,HSC)生长的“龛”,分泌造血生长因子(hematopoietic growth factor,HGF)和细胞外基质(extracellular matrix,ECM)等参与造血细胞的自我更新、增殖分化和归巢定位,在免疫调节方面也具有重要的作用。深入探讨基质细胞对骨髓造血功能的影响,从修复或重建骨髓微环境正常功能入手治疗造血功能损伤具有重要的理论价值和实际意义。 基质细胞由间充质干细胞(mesenchymal stem cell,MSC)分化而来,是一个包括成纤维细胞、内皮细胞、成骨细胞、脂肪细胞、巨噬细胞和网状细胞等成分复杂的异质细胞群。自1977年Dexter在体外培养出人骨髓基质细胞(human bone marrow stromal cells,hBMSCs)获得成功后,人们对hBMSCs进行了深入的研究。经实验研究和临床实践证实,hBMSCs体外培养扩增联合HSC回输是重建造血功能的有效方法。但hBMSCs来源受限,采集骨髓增加供者痛苦和风险,且细胞数量及增殖分化潜能随供者年龄增加而下降。自体移植中患者自身基质细胞存在异常,而异体移植亦有可能带来移植物抗宿主病(graft-versus-host disease,GVHD)等免疫相关问题,均限制了hBMSCs在临床上的广泛运用。 人脐血来源丰富,取材方便,具有未成熟的干/祖细胞比例高且免疫原性较低等特点,在多种造血系统恶性疾病临床治疗中具有潜在的应用价值。本课题组长期从事人脐血源基质细胞(human umbilical cord blood-derived stromal cells,hUCBDSCs)及脐血造血微环境的研究,前期研究通过特定的细胞因子使hUCBDSCs得以有效扩增,扩增后的hUCBDSCs在细胞成分和免疫表型上与hBMSCs相似,能够分泌表达多种细胞因子,具备造血基质细胞的基本特征。以hUCBDSCs为滋养层的培养体系能有效支持脐血CD34+细胞体外扩增,特别对于促巨核细胞集落形成单位(colony forming unit-megakaryocte,CFU-Mk)形成的作用明显优于hBMSCs,提示hUCBDSCs在促进巨核系增殖分化成熟方面可能具有重要的意义。深入探讨hUCBDSCs移植在体内支持和调控造血、重建造血微环境的作用可为造血功能损伤修复治疗提供新的思路。基于上述分析,本课题首先建立两种不同来源基质细胞滋养层(hUCBDSCs和hBMSCs)培养体系,采用CCK-8法和Transwell法分别观察两种基质细胞对脐血单个核细胞(human umbilical cord mononuclear cells,hUCB-MNCs)增殖、粘附和迁移的影响,并采用RT-PCR法检测hUCBDSCs对归巢相关分子mRNA的表达情况。在此基础上建立BABL/c小鼠造血微环境辐照损伤模型,采用hUCB-MNCs单移植,或分别联合两种不同来源基质细胞共移植的方法,比较观察两种基质细胞促进造血细胞体内归巢与植入、重建造血微环境及支持造血重建的作用,为安全有效的临床移植治疗提供新的辅助措施和手段。 方法: 1.体外构建hUCBDSCs和hBMSCs两种不同来源基质细胞滋养层培养体系。采用CCK-8法和Transwell法分别检测两种基质细胞对hUCB-MNCs体外增殖、粘附和迁移的影响;采用RT-PCR法检测hUCBDSCs对归巢相关因子(SDF-1、CXCR-4、ICAM-1、VCAM-1、HCAM、PECAM-1、Fn)mRNA的表达情况。 2.以近交系BABL/c小鼠作为受体鼠,经60COγ射线致死剂量8.5 Gy全身照射预处理后分别接受不同剂量hUCB-MNCs(2、4、6或8×10~6/只)单移植,或联合hUCBDSCs(2×10~6/只)共移植,移植后第6周流式细胞仪检测小鼠骨髓人源CD45+细胞植入率。 3.采用CM-DiI荧光染料预染hUCB-MNCs,辐照后BABL/c小鼠分别接受hUCB-MNCs(2×10~6/只)单移植,或联合两种不同来源基质细胞(2×10~6/只)共移植。激光共聚焦显微镜追踪观察移植后荧光标记hUCB-MNCs在小鼠体内的迁移分布情况,比较各组造血细胞归巢率。 4.辐照后小鼠分别接受hUCB-MNCs(2×10~6/只)单移植,或联合两种不同来源基质细胞(2×10~6/只)共移植。观察移植后各组小鼠存活情况,记录生存率;动态检测外周血血象恢复情况,骨髓组织病理切片观察骨髓病理变化;不同时相点计数各组小鼠骨髓成纤维细胞集落形成单位(CFU-F)、脾集落形成单位(CFU-S)、粒/巨噬细胞集落形成单位(CFU-GM)和巨核细胞集落形成单位(CFU-Mk)产率。 结果: 1. hUCBDSCs对脐血单个核细胞体外增殖、粘附和迁移能力的影响 同hBMSCs共培养组和hUCB-MNCs单独培养组相比较,hUCB-MNCs在hUCBDSCs共培养条件下增殖能力显著增强。两种基质细胞均能促进hUCB-MNCs的粘附,且共培养后hUCB-MNCs迁移能力也显著(P0.05)强于无基质细胞支持对照。hUCBDSCs明显表达与造血细胞归巢植入密切相关的粘附分子、细胞因子及受体(SDF-1、CXCR-4、ICAM-1、VCAM-1、HCAM、PECAM-1、Fn)mRNA,揭示其对造血细胞在体内的归巢和植入具有重要作用。 2. hUCBDSCs联合移植促进造血细胞归巢和植入 辐照后小鼠分别接受不同剂量hUCB-MNCs(2、4、6或8×10~6/只)单移植,或联合hUCBDSCs(2×10~6/只)共移植。采用不同剂量的hUCB-MNCs单移植后的植入率随hUCB-MNCs输注量增加而增长。hUCBDSCs联合移植能不同程度提高小鼠骨髓中人CD45~+细胞植入比例,尤其当输注低剂量hUCB-MNC(s2×10~6/只)时,hUCBDSCs共移植较单移植的植入率提高最为显著。激光共聚焦显微镜下观察CM-DiI标记的hUCB-MNCs在移植后2～3天主要归巢至骨髓和脾脏。移植后48小时,hUCBDSCs共移植组归巢率显著(P0.05)高于hBMSCs共移植组和单移植组,显示移植后早期hUCBDSCs能促进造血细胞向骨髓迁移归巢。 3.hUCBDSCs联合移植修复受损微环境,支持造血重建 两种基质细胞共移植组在移植后均能促进小鼠存活,血象恢复较快,在移植后28天内恢复至照射前水平。其中,hUCBDSCs共移植组血小板受抑程度较轻,回升也较快,并于移植后21天恢复至照射前水平;h BMSCs共移植组白细胞于移植后10天迅速回升,在此后恢复趋势高于hUCBDSCs共移植组;共移植两组间血红蛋白变化趋势无显著性差异。hUCBDSCs联合移植移植后促进骨髓组织恢复,重建受损微环境,提高CFUs(CFU-F,CFU-S,CFU-GM,CFU-Mk)产率,特别是CHU-Mk数量较h BMSCs联合移植增多,提示hUCBDSCs对于促巨核系增殖分化具有重要作用。 结论: 1. hUCBDSCs能促进脐血单个核细胞增殖、粘附和迁移,且促增殖能力较h BMSCs强。人脐血源基质细胞显著表达一些归巢相关因子的mRNA。 2. hUCBDSCs联合移植能提高移植后小鼠造血植入率,特别当造血细胞输注为低剂量时,这种作用更加显著。 3. hUCBDSCs联合移植能促进造血细胞早期迁移归巢至骨髓和脾脏,提高归巢效率。 4. hUCBDSCs联合移植能提高小鼠存活,促进移植后造血重建并修复受损微环境。
[Abstract]:Hematopoietic microenvironment (HIM) is an internal environment that supports and regulates the growth and development of haemopoietic stem/progenitor cell (HSPC). The integrity of its structure and function is an important link in maintaining normal hematopoietic function. Cells may participate in the self-renewal, proliferation, differentiation and homing of hematopoietic stem cells (HSCs), secrete hematopoietic growth factor (HGF) and extracellular matrix (ECM) through the formation of "niches" for the growth of hematopoietic stem cells (HSCs), and play an important role in immune regulation. To investigate the effect of stromal cells on hematopoietic function of bone marrow, it is of great theoretical value and practical significance to treat hematopoietic damage by repairing or reconstructing the normal function of bone marrow microenvironment.
Stromal cells, derived from mesenchymal stem cells (MSCs), are a complex heterogeneous group of cells including fibroblasts, endothelial cells, osteoblasts, adipocytes, macrophages and reticular cells. Human bone marrow stromal cells (hBMSCs) have been cultured in vitro by Dexter since 1977. After successful transplantation, hBMSCs were studied in depth. Experiments and clinical practice proved that hBMSCs in vitro culture and amplification combined with HSC reinfusion is an effective method for reconstructing hematopoietic function. However, the source of hBMSCs is limited. Bone marrow collection increases donor pain and risk, and cell number and proliferation and differentiation potential decrease with the increase of donor age. Autologous transplantation has abnormal stromal cells, and allograft-versus-host disease (GVHD) and other immune-related problems may occur in autologous transplantation, which limits the wide use of hBMSCs in clinical practice.
Human umbilical cord blood-derived stromal cells (hUCBDSCs) and umbilical cord blood have long been engaged in the clinical treatment of malignant hematopoietic diseases. Previous studies have shown that specific cytokines can effectively amplify hUCBDSCs. The amplified hUCBDSCs are similar to hBMSCs in cell composition and immunophenotype. They can secrete and express many cytokines and possess the basic characteristics of hematopoietic stromal cells. The culture system with hUCBDSCs as trophoblast can effectively support umbilical cord blood. CD34+ cell proliferation in vitro, especially for colony forming unit-megakaryocte (CFU-Mk) formation, is significantly superior to that of hBMSCs, suggesting that hUCBDSCs may play an important role in promoting the proliferation, differentiation and maturation of megakaryocytes. Based on the above analysis, two different culture systems of stromal cell trophoblasts (hUCBDSCs and hBMSCs) were established to observe the effects of two kinds of stromal cells on human umbilical cord mononuclear cells (HUCBDSCs) by CCK-8 and Transwell methods. The effects of proliferation, adhesion and migration of R cells, hUCB-MNCs, and the expression of homing-related molecules mRNA in hUCBDSCs were detected by RT-PCR. On this basis, the model of hematopoietic microenvironment irradiation injury in BABL/c mice was established. The two methods were compared and observed by single transplantation of hUCB-MNCs or co-transplantation of two different stromal cells. Stromal cells promote the homing and implantation of hematopoietic cells in vivo, reconstruct the hematopoietic microenvironment and support the hematopoietic reconstruction.
Method:
1. To construct the trophoblast culture system of hUCBDSCs and hBMSCs in vitro. CCK-8 method and Transwell method were used to detect the effects of two kinds of stromal cells on the proliferation, adhesion and migration of hUCB-MNCs in vitro; RT-PCR was used to detect the expression of homing-related factors (SDF-1, CXCR-4, ICAM-1, VCAM-1, HCAM, PECAM-1, Fn) mRNA. Situation.
2. Inbred BABL/c mice were subjected to different doses of hUCB-MNCs (2,4,6 or 8 65507
3. HUCB-MNCs were pre-stained with CM-DiI fluorescent dye. After irradiation, BABL/c mice received either single transplantation of hUCB-MNCs (2 x106/mouse) or co-transplantation of two different stromal cells (2 x106/mouse). Laser confocal microscopy was used to observe the migration and distribution of fluorescent labeled hUCB-MNCs in mice, and to compare the hematopoietic cells of each group. Nesting rate.
4. After irradiation, mice received either single transplantation of hUCB-MNCs (2 *10~6/mouse) or co-transplantation of two different stromal cells (2 *10~6/mouse). Survival was observed and survival rate was recorded. The recovery of peripheral blood picture was dynamically detected, and pathological changes of bone marrow tissue were observed. Rat bone marrow fibroblast colony forming unit (CFU-F), spleen colony forming unit (CFU-S), granulocyte/macrophage colony forming unit (CFU-GM) and megakaryocyte colony forming unit (CFU-Mk) yields.
Result:
Effect of 1. hUCBDSCs on proliferation, adhesion and migration of cord blood mononuclear cells in vitro
Compared with hUCB-MNCs co-culture group and hUCB-MNCs single culture group, hUCB-MNCs proliferation ability was significantly enhanced under the co-culture condition of hUCB-MNCs. Both stromal cells could promote the adhesion of hUCB-MNCs, and the migration ability of hUCB-MNCs after co-culture was also significantly stronger (P 0.05) than that of control without stromal cell support. Implantation of closely related adhesion molecules, cytokines and receptors (SDF-1, CXCR-4, ICAM-1, VCAM-1, HCAM, PECAM-1, Fn) mRNA reveals their important role in the homing and implantation of hematopoietic cells in vivo.
2. hUCBDSCs combined transplantation promotes homing and implantation of hematopoietic cells
After irradiation, mice received different doses of hUCB-MNCs (2,4,6 or 8 65507 When low-dose hUCB-MNC was infused, the implantation rate of co-transplantation of hUCBDSCs was significantly higher than that of single transplantation. And single transplantation group showed that hUCBDSCs could promote hematopoietic cells homing to bone marrow in early stage after transplantation.
3.hUCBDSCs combined transplantation to repair damaged microenvironment and support hematopoietic reconstitution
In the co-transplantation group, the platelet inhibition was mild and the platelet recovery was rapid, and the leukocytes in the co-transplantation group returned to the pre-irradiation level 21 days after transplantation. There was no significant difference in hemoglobin between the two groups. hUCBDSCs combined transplantation promoted bone marrow tissue recovery, reconstructed the damaged microenvironment, and increased the CFUs (CFU-F, CFU-S, CFU-GM, CFU-Mk) production rate, especially the number of CHU-Mk increased compared with the hUCBDSCs combined transplantation. S plays an important role in promoting proliferation and differentiation of megakaryocytes.
Conclusion:
1. hUCBDSCs can promote the proliferation, adhesion and migration of umbilical cord blood mononuclear cells, and the proliferation-promoting ability is stronger than that of H BMSCs. Human umbilical cord blood stromal cells significantly express the mRNA of some homing-related factors.
2. Combined transplantation of hUCBDSCs can increase the rate of hematopoietic implantation in mice after transplantation, especially when the dosage of hematopoietic cells is low.
3. hUCBDSCs combined transplantation can promote early migration of hematopoietic cells, homing to bone marrow and spleen, and improving homing efficiency.
4. hUCBDSCs combined transplantation can improve the survival of mice, promote hematopoietic reconstitution after transplantation and repair the damaged microenvironment.
【学位授予单位】：第三军医大学
【学位级别】：硕士
【学位授予年份】：2011
【分类号】：R329
本文编号：2225577
[Abstract]:Hematopoietic microenvironment (HIM) is an internal environment that supports and regulates the growth and development of haemopoietic stem/progenitor cell (HSPC). The integrity of its structure and function is an important link in maintaining normal hematopoietic function. Cells may participate in the self-renewal, proliferation, differentiation and homing of hematopoietic stem cells (HSCs), secrete hematopoietic growth factor (HGF) and extracellular matrix (ECM) through the formation of "niches" for the growth of hematopoietic stem cells (HSCs), and play an important role in immune regulation. To investigate the effect of stromal cells on hematopoietic function of bone marrow, it is of great theoretical value and practical significance to treat hematopoietic damage by repairing or reconstructing the normal function of bone marrow microenvironment.
Stromal cells, derived from mesenchymal stem cells (MSCs), are a complex heterogeneous group of cells including fibroblasts, endothelial cells, osteoblasts, adipocytes, macrophages and reticular cells. Human bone marrow stromal cells (hBMSCs) have been cultured in vitro by Dexter since 1977. After successful transplantation, hBMSCs were studied in depth. Experiments and clinical practice proved that hBMSCs in vitro culture and amplification combined with HSC reinfusion is an effective method for reconstructing hematopoietic function. However, the source of hBMSCs is limited. Bone marrow collection increases donor pain and risk, and cell number and proliferation and differentiation potential decrease with the increase of donor age. Autologous transplantation has abnormal stromal cells, and allograft-versus-host disease (GVHD) and other immune-related problems may occur in autologous transplantation, which limits the wide use of hBMSCs in clinical practice.
Human umbilical cord blood-derived stromal cells (hUCBDSCs) and umbilical cord blood have long been engaged in the clinical treatment of malignant hematopoietic diseases. Previous studies have shown that specific cytokines can effectively amplify hUCBDSCs. The amplified hUCBDSCs are similar to hBMSCs in cell composition and immunophenotype. They can secrete and express many cytokines and possess the basic characteristics of hematopoietic stromal cells. The culture system with hUCBDSCs as trophoblast can effectively support umbilical cord blood. CD34+ cell proliferation in vitro, especially for colony forming unit-megakaryocte (CFU-Mk) formation, is significantly superior to that of hBMSCs, suggesting that hUCBDSCs may play an important role in promoting the proliferation, differentiation and maturation of megakaryocytes. Based on the above analysis, two different culture systems of stromal cell trophoblasts (hUCBDSCs and hBMSCs) were established to observe the effects of two kinds of stromal cells on human umbilical cord mononuclear cells (HUCBDSCs) by CCK-8 and Transwell methods. The effects of proliferation, adhesion and migration of R cells, hUCB-MNCs, and the expression of homing-related molecules mRNA in hUCBDSCs were detected by RT-PCR. On this basis, the model of hematopoietic microenvironment irradiation injury in BABL/c mice was established. The two methods were compared and observed by single transplantation of hUCB-MNCs or co-transplantation of two different stromal cells. Stromal cells promote the homing and implantation of hematopoietic cells in vivo, reconstruct the hematopoietic microenvironment and support the hematopoietic reconstruction.
Method:
1. To construct the trophoblast culture system of hUCBDSCs and hBMSCs in vitro. CCK-8 method and Transwell method were used to detect the effects of two kinds of stromal cells on the proliferation, adhesion and migration of hUCB-MNCs in vitro; RT-PCR was used to detect the expression of homing-related factors (SDF-1, CXCR-4, ICAM-1, VCAM-1, HCAM, PECAM-1, Fn) mRNA. Situation.
2. Inbred BABL/c mice were subjected to different doses of hUCB-MNCs (2,4,6 or 8 65507
3. HUCB-MNCs were pre-stained with CM-DiI fluorescent dye. After irradiation, BABL/c mice received either single transplantation of hUCB-MNCs (2 x106/mouse) or co-transplantation of two different stromal cells (2 x106/mouse). Laser confocal microscopy was used to observe the migration and distribution of fluorescent labeled hUCB-MNCs in mice, and to compare the hematopoietic cells of each group. Nesting rate.
4. After irradiation, mice received either single transplantation of hUCB-MNCs (2 *10~6/mouse) or co-transplantation of two different stromal cells (2 *10~6/mouse). Survival was observed and survival rate was recorded. The recovery of peripheral blood picture was dynamically detected, and pathological changes of bone marrow tissue were observed. Rat bone marrow fibroblast colony forming unit (CFU-F), spleen colony forming unit (CFU-S), granulocyte/macrophage colony forming unit (CFU-GM) and megakaryocyte colony forming unit (CFU-Mk) yields.
Result:
Effect of 1. hUCBDSCs on proliferation, adhesion and migration of cord blood mononuclear cells in vitro
Compared with hUCB-MNCs co-culture group and hUCB-MNCs single culture group, hUCB-MNCs proliferation ability was significantly enhanced under the co-culture condition of hUCB-MNCs. Both stromal cells could promote the adhesion of hUCB-MNCs, and the migration ability of hUCB-MNCs after co-culture was also significantly stronger (P 0.05) than that of control without stromal cell support. Implantation of closely related adhesion molecules, cytokines and receptors (SDF-1, CXCR-4, ICAM-1, VCAM-1, HCAM, PECAM-1, Fn) mRNA reveals their important role in the homing and implantation of hematopoietic cells in vivo.
2. hUCBDSCs combined transplantation promotes homing and implantation of hematopoietic cells
After irradiation, mice received different doses of hUCB-MNCs (2,4,6 or 8 65507 When low-dose hUCB-MNC was infused, the implantation rate of co-transplantation of hUCBDSCs was significantly higher than that of single transplantation. And single transplantation group showed that hUCBDSCs could promote hematopoietic cells homing to bone marrow in early stage after transplantation.
3.hUCBDSCs combined transplantation to repair damaged microenvironment and support hematopoietic reconstitution
In the co-transplantation group, the platelet inhibition was mild and the platelet recovery was rapid, and the leukocytes in the co-transplantation group returned to the pre-irradiation level 21 days after transplantation. There was no significant difference in hemoglobin between the two groups. hUCBDSCs combined transplantation promoted bone marrow tissue recovery, reconstructed the damaged microenvironment, and increased the CFUs (CFU-F, CFU-S, CFU-GM, CFU-Mk) production rate, especially the number of CHU-Mk increased compared with the hUCBDSCs combined transplantation. S plays an important role in promoting proliferation and differentiation of megakaryocytes.
Conclusion:
1. hUCBDSCs can promote the proliferation, adhesion and migration of umbilical cord blood mononuclear cells, and the proliferation-promoting ability is stronger than that of H BMSCs. Human umbilical cord blood stromal cells significantly express the mRNA of some homing-related factors.
2. Combined transplantation of hUCBDSCs can increase the rate of hematopoietic implantation in mice after transplantation, especially when the dosage of hematopoietic cells is low.
3. hUCBDSCs combined transplantation can promote early migration of hematopoietic cells, homing to bone marrow and spleen, and improving homing efficiency.
4. hUCBDSCs combined transplantation can improve the survival of mice, promote hematopoietic reconstitution after transplantation and repair the damaged microenvironment.
【学位授予单位】：第三军医大学
【学位级别】：硕士
【学位授予年份】：2011
【分类号】：R329
【共引文献】
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