间充质干细胞（MSCs）用于肿瘤化疗辅助治疗及与肿瘤生长关系的实验研究
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摘要
间充质干细胞（mesenchymal stem cells，MSCs）是一类具有多项分化潜能的成体干细胞，在细胞治疗和再生医学领域具有巨大的应用潜力。但是，MSCs在肿瘤化疗领域的应用潜力至今尚不清楚，本文拟研究MSCs作为肿瘤化疗的辅助治疗手段，缓解化疗导致的组织损伤，并研究影响MSCs与肿瘤生长的因素。
我们分别通过组织块种植法、胶原酶消化法、梯度密度离心法从脐带、脂肪、骨髓中分离出MSCs，流式检测显示三种MSCs均表达CD29，CD44，CD73，HLA-ABC；不表达CD14，CD31，CD34，CD45，HLA-DR。在合适的诱导培养基诱导下，三种MSCs均可以分化为成骨细胞和脂肪细胞。
我们开发了一种以海藻糖为核心成分的MSCs4℃保护液。我们发现40mmol/L海藻糖组具有最佳的保护效果，MSCs在保存7天后，台盼蓝检测显示有92.7±1.5%存活，在保存3周后仍有70%的存活率。MSCs在保存3周后与保存前相比具有相同的免疫表型，增殖与分化能力。
我们以小鼠Lewis肺癌和人结肠癌两种荷瘤动物模型为研究对象，采用连续三天给予化疗药阿霉素（Adriamycin，ADM)接着尾静脉注射MSCs的治疗方法，结果显示MSCs可以缓解ADM导致的骨髓抑制、心肌损伤，减轻ADM引发的小肠绒毛细胞凋亡，减少体重下降程度，提高致死剂量ADM下小鼠的生存率。同时，尾静脉注射MSCs不影响化疗药对Lewis肺癌和Lovo结肠癌肿瘤的杀伤效果，并且，显著抑制Lewis肺癌的肺转移。我们的结果显示，对于某些类型的肿瘤，MSCs治疗可以作为肿瘤化疗的辅助治疗方法。
我们分析了影响MSCs与肿瘤生长的因素，发现脐带MSCs对肺癌细胞如A549，95D等的迁移具有抑制作用，对于乳腺癌细胞如MDA-MB-231，MCF-7等具有促进作用。脐带MSCs抑制低转移肝癌细胞HepG2的迁移，却促进高转移肝癌细胞LM-3和97H的迁移。不同来源的MSCs对于相同肿瘤细胞的作用基本相同。我们通过自然传代和H2O2诱导的方法分别获得了衰老MSCs。与正常MSCs相比，衰老MSCs的分泌型发生显著变化，如IL-6升高了40余倍。衰老MSCs显著促进肿瘤细胞的增殖与迁移且与IL-6的分泌升高密切相关。我们以乳腺癌细胞MDA-MB-231为研究对象做裸鼠成瘤实验，发现衰老MSCs与肿瘤细胞共移植后，可以显著促进肿瘤的生长，免疫组化分析显示衰老MSCs可以促进肿瘤组织新生血管的生成。
Mesenchymal stem cells (MSCs), a subset of multipotential adult stem cells,hold great therapeutic potential in cell therapy and regenerative medicine. However,their therapeutic potential against chemotherapy-induced side effects remains unclear.In the present study, we evaluated the prophylactic or therapeutic action ofhUC-MSCs on chemotherapy agent Doxorubicin-induced side effects in two differenttumor models and analyzed factors that impact MSCs and tumor growth.
We isolated MSCs from umbilical cord, adipose tissue, bone marrow throughminced tissue planting, collagenase digestion and density gradient centrifugationrespectively. FACS examination showed that MSCs from different tissue originshowed similar immunophenotype, i.e. positive for CD29，CD44，CD73，HLA-ABCwhereas negative for CD14，CD31，CD34，CD45，HLA-DR. Given appropriatemedium, MSCs were able to differentiate into osteocytes and adipocytes.
We developed a solution formula that could preserve MSCs at4℃for up to3weeks. In the solution, trehalose is a key ingredient for maintaining survival of MSCs.Among the concentrations investigated,40mM trehalose showed the best outcomewith the viability maintained more than92.7±1.5%for7days. Cells preserved in thesolution formula for3weeks still remained about70%viability, and produced resultssimilar to those of freshly harvested hMSCs in terms of growth kinetics, expressionprofile of cell surface antigens and differentiation potential.
We treated murine Lewis lung carcinoma and xenograft human colon tumorswith Doxorubicin (DOX) for three consecutive days followed by one i.v. injection ofhUC-MSCs for several cycles. MSCs treatment could mitigate DOX-inducedcardiomyopathy, reduce the extent of DOX-induced apoptosis in intestinal crypts,suppress the body weight loss in mice treated with DOX and increase the survival rateof mice treated with lethal dose of DOX. The examination of hematologicalparameters indicated a moderate recovery in MSC injected mice. Systemicadministration of MSC did not increase the growth of murine Lewis lung carcinomacell (LLC) and human colon carcinoma in vivo while strongly inhibited the lungmetastases of LLC cell. Our observations suggest that MSCs can be used as auxiliarymeans in chemotherapy for certain tumor types.
We analyzed factors that impact MSCs and tumor growth. Our results showedthat human umbilical cord MSCs could inhibit the migration of lung cancer cell linessuch as A549and95D while promote migration of breast cancer cell lines asMDA-MB-231and MCF-7. For hepatoma cell lines, MSCs could suppress the migration of low metastatic cell line HepG2while facilitate the movement of highmetastatic cell line LM-3and97H. MSCs from different tissue origin showed similarimpact on the same tumor cell line. We got senescent MSCs through replicationsenescence and H2O2induction which showed dramatically different cytokinessecretion profile like40times increased for IL-6secretion. Senescent MSCs couldpromote cancer cell proliferation and migration through IL-6dependent manner.
The effect of senescent MSCs on tumor cell in vivo was analyzed byco-implantation with breast cancer cell MDA-MB-231subcutaneously into nude mice.Our results demonstrated that H2O2induced MSCs could significantly promote tumorgrowth. Immunohistochemical analyzation suggested senescent MSCs could improvetumor angiogenesis.
我们分别通过组织块种植法、胶原酶消化法、梯度密度离心法从脐带、脂肪、骨髓中分离出MSCs，流式检测显示三种MSCs均表达CD29，CD44，CD73，HLA-ABC；不表达CD14，CD31，CD34，CD45，HLA-DR。在合适的诱导培养基诱导下，三种MSCs均可以分化为成骨细胞和脂肪细胞。
我们开发了一种以海藻糖为核心成分的MSCs4℃保护液。我们发现40mmol/L海藻糖组具有最佳的保护效果，MSCs在保存7天后，台盼蓝检测显示有92.7±1.5%存活，在保存3周后仍有70%的存活率。MSCs在保存3周后与保存前相比具有相同的免疫表型，增殖与分化能力。
我们以小鼠Lewis肺癌和人结肠癌两种荷瘤动物模型为研究对象，采用连续三天给予化疗药阿霉素（Adriamycin，ADM)接着尾静脉注射MSCs的治疗方法，结果显示MSCs可以缓解ADM导致的骨髓抑制、心肌损伤，减轻ADM引发的小肠绒毛细胞凋亡，减少体重下降程度，提高致死剂量ADM下小鼠的生存率。同时，尾静脉注射MSCs不影响化疗药对Lewis肺癌和Lovo结肠癌肿瘤的杀伤效果，并且，显著抑制Lewis肺癌的肺转移。我们的结果显示，对于某些类型的肿瘤，MSCs治疗可以作为肿瘤化疗的辅助治疗方法。
我们分析了影响MSCs与肿瘤生长的因素，发现脐带MSCs对肺癌细胞如A549，95D等的迁移具有抑制作用，对于乳腺癌细胞如MDA-MB-231，MCF-7等具有促进作用。脐带MSCs抑制低转移肝癌细胞HepG2的迁移，却促进高转移肝癌细胞LM-3和97H的迁移。不同来源的MSCs对于相同肿瘤细胞的作用基本相同。我们通过自然传代和H2O2诱导的方法分别获得了衰老MSCs。与正常MSCs相比，衰老MSCs的分泌型发生显著变化，如IL-6升高了40余倍。衰老MSCs显著促进肿瘤细胞的增殖与迁移且与IL-6的分泌升高密切相关。我们以乳腺癌细胞MDA-MB-231为研究对象做裸鼠成瘤实验，发现衰老MSCs与肿瘤细胞共移植后，可以显著促进肿瘤的生长，免疫组化分析显示衰老MSCs可以促进肿瘤组织新生血管的生成。
Mesenchymal stem cells (MSCs), a subset of multipotential adult stem cells,hold great therapeutic potential in cell therapy and regenerative medicine. However,their therapeutic potential against chemotherapy-induced side effects remains unclear.In the present study, we evaluated the prophylactic or therapeutic action ofhUC-MSCs on chemotherapy agent Doxorubicin-induced side effects in two differenttumor models and analyzed factors that impact MSCs and tumor growth.
We isolated MSCs from umbilical cord, adipose tissue, bone marrow throughminced tissue planting, collagenase digestion and density gradient centrifugationrespectively. FACS examination showed that MSCs from different tissue originshowed similar immunophenotype, i.e. positive for CD29，CD44，CD73，HLA-ABCwhereas negative for CD14，CD31，CD34，CD45，HLA-DR. Given appropriatemedium, MSCs were able to differentiate into osteocytes and adipocytes.
We developed a solution formula that could preserve MSCs at4℃for up to3weeks. In the solution, trehalose is a key ingredient for maintaining survival of MSCs.Among the concentrations investigated,40mM trehalose showed the best outcomewith the viability maintained more than92.7±1.5%for7days. Cells preserved in thesolution formula for3weeks still remained about70%viability, and produced resultssimilar to those of freshly harvested hMSCs in terms of growth kinetics, expressionprofile of cell surface antigens and differentiation potential.
We treated murine Lewis lung carcinoma and xenograft human colon tumorswith Doxorubicin (DOX) for three consecutive days followed by one i.v. injection ofhUC-MSCs for several cycles. MSCs treatment could mitigate DOX-inducedcardiomyopathy, reduce the extent of DOX-induced apoptosis in intestinal crypts,suppress the body weight loss in mice treated with DOX and increase the survival rateof mice treated with lethal dose of DOX. The examination of hematologicalparameters indicated a moderate recovery in MSC injected mice. Systemicadministration of MSC did not increase the growth of murine Lewis lung carcinomacell (LLC) and human colon carcinoma in vivo while strongly inhibited the lungmetastases of LLC cell. Our observations suggest that MSCs can be used as auxiliarymeans in chemotherapy for certain tumor types.
We analyzed factors that impact MSCs and tumor growth. Our results showedthat human umbilical cord MSCs could inhibit the migration of lung cancer cell linessuch as A549and95D while promote migration of breast cancer cell lines asMDA-MB-231and MCF-7. For hepatoma cell lines, MSCs could suppress the migration of low metastatic cell line HepG2while facilitate the movement of highmetastatic cell line LM-3and97H. MSCs from different tissue origin showed similarimpact on the same tumor cell line. We got senescent MSCs through replicationsenescence and H2O2induction which showed dramatically different cytokinessecretion profile like40times increased for IL-6secretion. Senescent MSCs couldpromote cancer cell proliferation and migration through IL-6dependent manner.
The effect of senescent MSCs on tumor cell in vivo was analyzed byco-implantation with breast cancer cell MDA-MB-231subcutaneously into nude mice.Our results demonstrated that H2O2induced MSCs could significantly promote tumorgrowth. Immunohistochemical analyzation suggested senescent MSCs could improvetumor angiogenesis.
引文
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