Transplantation of insulin-producing cells derived from human mesenchymal stromal/stem cells into diabetic humanized mice

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

Research output: Contribution to journalArticlepeer-review

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: [Figure not available: see fulltext.].

Original languageEnglish (US)
Article number350
JournalStem Cell Research and Therapy
Volume13
Issue number1
DOIs
StatePublished - Dec 2022

Keywords

  • Diabetes
  • Differentiation
  • Humanized mice
  • Insulin producing cells
  • Mesenchymal stromal cells
  • Streptozotocin
  • Transplantation

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Molecular Medicine
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Cell Biology

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