Transplantation of insulin-producing cells derived from human mesenchymal stromal/stem cells into diabetic humanized mice
Abstract Background The purpose of this study was to investigate allogenic immune responses following the transplantation of insulin-producing cells (IPCs) differentiated from human adipose tissue-derived stem cells (hAT-MSCs) into humanized mice. Methods hAT-MSCs were isolated from liposuction aspi...
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| Format: | Article |
| Language: | English |
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BMC
2022-07-01
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| Series: | Stem Cell Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13287-022-03048-y |
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| author | Mohamed A. Ghoneim Mahmoud M. Gabr Ayman F. Refaie Sawsan M. El-Halawani Mohga M. Al-issawi Batoul L. Elbassiouny Mai A. Abd El Kader Amani M. Ismail Mona F. Zidan Mary S. Karras Raghda W. Magar Sherry M. Khater Sylvia A. Ashamallah Mahmoud M. Zakaria Malgorzata Kloc |
| author_facet | Mohamed A. Ghoneim Mahmoud M. Gabr Ayman F. Refaie Sawsan M. El-Halawani Mohga M. Al-issawi Batoul L. Elbassiouny Mai A. Abd El Kader Amani M. Ismail Mona F. Zidan Mary S. Karras Raghda W. Magar Sherry M. Khater Sylvia A. Ashamallah Mahmoud M. Zakaria Malgorzata Kloc |
| author_sort | Mohamed A. Ghoneim |
| collection | DOAJ |
| description | Abstract Background The purpose of this study was to investigate allogenic immune responses following the transplantation of insulin-producing cells (IPCs) differentiated from human adipose tissue-derived stem cells (hAT-MSCs) into humanized mice. Methods hAT-MSCs were isolated from liposuction aspirates obtained from HLA-A2-negative healthy donors. These cells were expanded and differentiated into IPCs. HLA-A2-positive humanized mice (NOG-EXL) were divided into 4 groups: diabetic mice transplanted with IPCs, diabetic but nontransplanted mice, nondiabetic mice transplanted with IPCs and normal untreated mice. Three million differentiated cells were transplanted under the renal capsule. Animals were followed-up to determine their weight, glucose levels (2-h postprandial), and human and mouse insulin levels. The mice were euthanized 6–8 weeks posttransplant. The kidneys were explanted for immunohistochemical studies. Blood, spleen and bone marrow samples were obtained to determine the proportion of immune cell subsets (CD4+, CD8+, CD16+, CD19+ and CD69+), and the expression levels of HLA-ABC and HLA-DR. Results Following STZ induction, blood glucose levels increased sharply and were then normalized within 2 weeks after cell transplantation. In these animals, human insulin levels were measurable while mouse insulin levels were negligible throughout the observation period. Immunostaining of cell-bearing kidneys revealed sparse CD45+ cells. Immunolabeling and flow cytometry of blood, bone marrow and splenic samples obtained from the 3 groups of animals did not reveal a significant difference in the proportions of immune cell subsets or in the expression levels of HLA-ABC and HLA-DR. Conclusion Transplantation of IPCs derived from allogenic hAT-MSCs into humanized mice was followed by a muted allogenic immune response that did not interfere with the functionality of the engrafted cells. Our findings suggest that such allogenic cells could offer an opportunity for cell therapy for insulin-dependent diabetes without immunosuppression, encapsulation or gene manipulations. Graphical Abstract |
| first_indexed | 2024-04-14T07:33:03Z |
| format | Article |
| id | doaj.art-7c6b6aea704b486a939175f63d3eb9f7 |
| institution | Directory Open Access Journal |
| issn | 1757-6512 |
| language | English |
| last_indexed | 2024-04-14T07:33:03Z |
| publishDate | 2022-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Stem Cell Research & Therapy |
| spelling | doaj.art-7c6b6aea704b486a939175f63d3eb9f72022-12-22T02:05:48ZengBMCStem Cell Research & Therapy1757-65122022-07-0113111610.1186/s13287-022-03048-yTransplantation of insulin-producing cells derived from human mesenchymal stromal/stem cells into diabetic humanized miceMohamed A. Ghoneim0Mahmoud M. Gabr1Ayman F. Refaie2Sawsan M. El-Halawani3Mohga M. Al-issawi4Batoul L. Elbassiouny5Mai A. Abd El Kader6Amani M. Ismail7Mona F. Zidan8Mary S. Karras9Raghda W. Magar10Sherry M. Khater11Sylvia A. Ashamallah12Mahmoud M. Zakaria13Malgorzata Kloc14Urology Department, Urology and Nephrology CenterBiotechnology Department, Urology and Nephrology CenterNephrology Department, Urology and Nephrology CenterBiotechnology Department, Urology and Nephrology CenterBiotechnology Department, Urology and Nephrology CenterBiotechnology Department, Urology and Nephrology CenterBiotechnology Department, Urology and Nephrology CenterImmunology Department, Urology and Nephrology CenterMicrobiology and Immunology Research Program, Children’s Hospital 57357Immunology Department, Urology and Nephrology CenterImmunology Department, Urology and Nephrology CenterPathology Department, Urology and Nephrology CenterPathology Department, Urology and Nephrology CenterBiotechnology Department, Urology and Nephrology CenterThe Houston Methodist Research InstituteAbstract Background The purpose of this study was to investigate allogenic immune responses following the transplantation of insulin-producing cells (IPCs) differentiated from human adipose tissue-derived stem cells (hAT-MSCs) into humanized mice. Methods hAT-MSCs were isolated from liposuction aspirates obtained from HLA-A2-negative healthy donors. These cells were expanded and differentiated into IPCs. HLA-A2-positive humanized mice (NOG-EXL) were divided into 4 groups: diabetic mice transplanted with IPCs, diabetic but nontransplanted mice, nondiabetic mice transplanted with IPCs and normal untreated mice. Three million differentiated cells were transplanted under the renal capsule. Animals were followed-up to determine their weight, glucose levels (2-h postprandial), and human and mouse insulin levels. The mice were euthanized 6–8 weeks posttransplant. The kidneys were explanted for immunohistochemical studies. Blood, spleen and bone marrow samples were obtained to determine the proportion of immune cell subsets (CD4+, CD8+, CD16+, CD19+ and CD69+), and the expression levels of HLA-ABC and HLA-DR. Results Following STZ induction, blood glucose levels increased sharply and were then normalized within 2 weeks after cell transplantation. In these animals, human insulin levels were measurable while mouse insulin levels were negligible throughout the observation period. Immunostaining of cell-bearing kidneys revealed sparse CD45+ cells. Immunolabeling and flow cytometry of blood, bone marrow and splenic samples obtained from the 3 groups of animals did not reveal a significant difference in the proportions of immune cell subsets or in the expression levels of HLA-ABC and HLA-DR. Conclusion Transplantation of IPCs derived from allogenic hAT-MSCs into humanized mice was followed by a muted allogenic immune response that did not interfere with the functionality of the engrafted cells. Our findings suggest that such allogenic cells could offer an opportunity for cell therapy for insulin-dependent diabetes without immunosuppression, encapsulation or gene manipulations. Graphical Abstracthttps://doi.org/10.1186/s13287-022-03048-yMesenchymal stromal cellsDifferentiationTransplantationHumanized miceInsulin producing cellsDiabetes |
| spellingShingle | Mohamed A. Ghoneim Mahmoud M. Gabr Ayman F. Refaie Sawsan M. El-Halawani Mohga M. Al-issawi Batoul L. Elbassiouny Mai A. Abd El Kader Amani M. Ismail Mona F. Zidan Mary S. Karras Raghda W. Magar Sherry M. Khater Sylvia A. Ashamallah Mahmoud M. Zakaria Malgorzata Kloc Transplantation of insulin-producing cells derived from human mesenchymal stromal/stem cells into diabetic humanized mice Stem Cell Research & Therapy Mesenchymal stromal cells Differentiation Transplantation Humanized mice Insulin producing cells Diabetes |
| title | Transplantation of insulin-producing cells derived from human mesenchymal stromal/stem cells into diabetic humanized mice |
| title_full | Transplantation of insulin-producing cells derived from human mesenchymal stromal/stem cells into diabetic humanized mice |
| title_fullStr | Transplantation of insulin-producing cells derived from human mesenchymal stromal/stem cells into diabetic humanized mice |
| title_full_unstemmed | Transplantation of insulin-producing cells derived from human mesenchymal stromal/stem cells into diabetic humanized mice |
| title_short | Transplantation of insulin-producing cells derived from human mesenchymal stromal/stem cells into diabetic humanized mice |
| title_sort | transplantation of insulin producing cells derived from human mesenchymal stromal stem cells into diabetic humanized mice |
| topic | Mesenchymal stromal cells Differentiation Transplantation Humanized mice Insulin producing cells Diabetes |
| url | https://doi.org/10.1186/s13287-022-03048-y |
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