Islet-Like Structures Generated In Vitro from Adult Human Liver Stem Cells Revert Hyperglycemia in Diabetic SCID Mice
| العنوان: | Islet-Like Structures Generated In Vitro from Adult Human Liver Stem Cells Revert Hyperglycemia in Diabetic SCID Mice |
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| المؤلفون: | Giovanni Camussi, Victor Navarro-Tableros, Maria Chiara Deregibus, Sara Giunti, Marta Tapparo, Adriana Pitino, Yonathan Gomez, Ciro Tetta, Maria Felice Brizzi, Chiara Pasquino, Camillo Ricordi, Chiara Gai |
| المصدر: | Stem Cell Reviews |
| بيانات النشر: | Springer US, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Male, Cancer Research, medicine.medical_treatment, Cellular differentiation, Liver Stem Cell, Mice, SCID, 0302 clinical medicine, Insulin-Secreting Cells, Protamines, Liver stem cells, C-Peptide, Stem Cells, Diabetes, Cell Differentiation, medicine.anatomical_structure, Phenotype, Liver, 030220 oncology & carcinogenesis, Stem cell, Pancreas, 3D culture, Adult, medicine.medical_specialty, Pancreatic islets, Diabetete Tipo 1, Biology, Article, Pancreatic β cells, Diabetes Mellitus, Experimental, 03 medical and health sciences, Islets of Langerhans, In vivo, Internal medicine, Spheroids, Cellular, medicine, Animals, Humans, Insulin-producing stem cells, Insulin, cellule staminali, Cell Biology, Transplantation, 030104 developmental biology, Endocrinology, Glucose, Gene Expression Regulation, Diabetete Tipo 1, cellule staminali, Hyperglycemia, Biomarkers |
| الوصف: | A potential therapeutic strategy for diabetes is the transplantation of induced-insulin secreting cells. Based on the common embryonic origin of liver and pancreas, we studied the potential of adult human liver stem-like cells (HLSC) to generate in vitro insulin-producing 3D spheroid structures (HLSC-ILS). HLSC-ILS were generated by a one-step protocol based on charge dependent aggregation of HLSC induced by protamine. 3D aggregation promoted the spontaneous differentiation into cells expressing insulin and several key markers of pancreatic β cells. HLSC-ILS showed endocrine granules similar to those seen in human β cells. In static and dynamic in vitro conditions, such structures produced C-peptide after stimulation with high glucose. HLSC-ILS significantly reduced hyperglycemia and restored a normo-glycemic profile when implanted in streptozotocin-diabetic SCID mice. Diabetic mice expressed human C-peptide and very low or undetectable levels of murine C-peptide. Hyperglycemia and a diabetic profile were restored after HLSC-ISL explant. The gene expression profile of in vitro generated HLSC-ILS showed a differentiation from HLSC profile and an endocrine commitment with the enhanced expression of several markers of β cell differentiation. The comparative analysis of gene expression profiles after 2 and 4 weeks of in vivo implantation showed a further β-cell differentiation, with a genetic profile still immature but closer to that of human islets. In conclusion, protamine-induced spheroid aggregation of HLSC triggers a spontaneous differentiation to an endocrine phenotype. Although the in vitro differentiated HLSC-ILS were immature, they responded to high glucose with insulin secretion and in vivo reversed hyperglycemia in diabetic SCID mice. Electronic supplementary material The online version of this article (10.1007/s12015-018-9845-6) contains supplementary material, which is available to authorized users. |
| اللغة: | English |
| تدمد: | 1558-6804 1550-8943 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e7e7749facf87c233cf2afc11efd4bbdTest http://europepmc.org/articles/PMC6510809Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....e7e7749facf87c233cf2afc11efd4bbd |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15586804 15508943 |
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