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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2022-07-26

AUTHORS

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

ABSTRACT

BackgroundThe 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.MethodshAT-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.ResultsFollowing 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.ConclusionTransplantation 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 More... »

PAGES

350

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/s13287-022-03048-y

DOI

http://dx.doi.org/10.1186/s13287-022-03048-y

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1149784326

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/35883190


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23 schema:description BackgroundThe 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.MethodshAT-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.ResultsFollowing 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.ConclusionTransplantation 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
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30 CD45
31 HLA-A2
32 HLA-ABC
33 HLA-DR
34 STZ induction
35 adipose tissue-derived stem cells
36 allogenic cells
37 allogenic immune response
38 animals
39 aspirates
40 blood
41 blood glucose levels
42 bone marrow
43 bone marrow samples
44 capsule
45 cell subsets
46 cell therapy
47 cell transplantation
48 cells
49 cytometry
50 cytometry of blood
51 diabetes
52 diabetic mice
53 differences
54 differentiated cells
55 donors
56 encapsulation
57 engrafted cells
58 expression levels
59 findings
60 functionality
61 gene manipulation
62 glucose levels
63 group
64 groups of animals
65 hAT-MSCs
66 healthy donors
67 human adipose tissue-derived stem cells
68 human insulin levels
69 human mesenchymal stromal/stem cells
70 humanized mice
71 humans
72 immune cell subsets
73 immune response
74 immunohistochemical study
75 immunosuppression
76 induction
77 insulin levels
78 insulin-dependent diabetes
79 insulin-producing cells
80 kidney
81 levels
82 liposuction aspirates
83 manipulation
84 marrow
85 marrow samples
86 mesenchymal stromal/stem cells
87 mice
88 nondiabetic mice
89 normal untreated mice
90 observation period
91 opportunities
92 period
93 proportion
94 purpose
95 renal capsule
96 response
97 samples
98 significant differences
99 spleen
100 splenic samples
101 stem cells
102 stromal/stem cells
103 study
104 subset
105 therapy
106 tissue-derived stem cells
107 transplantation
108 untreated mice
109 weeks
110 weight
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