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Gene Modification and Three-Dimensional Scaffolds as Novel Tools to Allow the Use of Postnatal Thymic Epithelial Cells for Thymus Regeneration Approaches
- Source :
- Stem Cells Translational Medicine, Vol 8, Iss 10, Pp 1107-1122 (2019), Stem cells (Dayt. Ohio, Online) 8 (2019): 1107–1122. doi:10.1002/sctm.18-0218, info:cnr-pdr/source/autori:Bortolomai I.; Sandri M.; Draghici E.; Fontana E.; Campodoni E.; Marcovecchio G.E.; Ferrua F.; Perani L.; Spinelli A.; Canu T.; Catucci M.; Di Tomaso T.; Sergi Sergi L.; Esposito A.; Lombardo A.; Naldini L.; Tampieri A.; Hollander G.A.; Villa A.; Bosticardo M./titolo:Gene Modification and Three-Dimensional Scaffolds as Novel Tools to Allow the Use of Postnatal Thymic Epithelial Cells for Thymus Regeneration Approaches/doi:10.1002%2Fsctm.18-0218/rivista:Stem cells (Dayt. Ohio, Online)/anno:2019/pagina_da:1107/pagina_a:1122/intervallo_pagine:1107–1122/volume:8, Stem Cells Translational Medicine
- Publication Year :
- 2019
- Publisher :
- Oxford University Press (OUP), 2019.
-
Abstract
- Defective functionality of thymic epithelial cells (TECs), due to genetic mutations or injuring causes, results in altered T-cell development, leading to immunodeficiency or autoimmunity. These defects cannot be corrected by hematopoietic stem cell transplantation (HSCT), and thymus transplantation has not yet been demonstrated to be fully curative. Here, we provide proof of principle of a novel approach toward thymic regeneration, involving the generation of thymic organoids obtained by seeding gene-modified postnatal murine TECs into three-dimensional (3D) collagen type I scaffolds mimicking the thymic ultrastructure. To this end, freshly isolated TECs were transduced with a lentiviral vector system, allowing for doxycycline-induced Oct4 expression. Transient Oct4 expression promoted TECs expansion without drastically changing the cell lineage identity of adult TECs, which retain the expression of important molecules for thymus functionality such as Foxn1, Dll4, Dll1, and AIRE. Oct4-expressing TECs (iOCT4 TEC) were able to grow into 3D collagen type I scaffolds both in vitro and in vivo, demonstrating that the collagen structure reproduced a 3D environment similar to the thymic extracellular matrix, perfectly recognized by TECs. In vivo results showed that thymic organoids transplanted subcutaneously in athymic nude mice were vascularized but failed to support thymopoiesis because of their limited in vivo persistence. These findings provide evidence that gene modification, in combination with the usage of 3D biomimetic scaffolds, may represent a novel approach allowing the use of postnatal TECs for thymic regeneration. Stem Cells Translational Medicine 2019;8:1107–1122
- Subjects :
- Thymic epithelial cell
0301 basic medicine
Medicine (General)
medicine.medical_treatment
education
Mice, Nude
Thymus Gland
Biology
Viral vector
Extracellular matrix
Mice
03 medical and health sciences
R5-920
0302 clinical medicine
In vivo
Tissue Engineering and Regenerative Medicine
Organoid
medicine
Animals
Regeneration
Cell Lineage
Thymic epithelial cells
QH573-671
Thymic regeneration
Regeneration (biology)
FOXN1
Cell Differentiation
hemic and immune systems
Cell Biology
General Medicine
epithelial cells
Cell biology
3D collagen scaffolds
030104 developmental biology
Thymus transplantation
3D collagen scaffold
Lentiviral vector
Stem cell
Cytology
tissues
030217 neurology & neurosurgery
Developmental Biology
Subjects
Details
- ISSN :
- 21576580 and 21576564
- Volume :
- 8
- Database :
- OpenAIRE
- Journal :
- Stem Cells Translational Medicine
- Accession number :
- edsair.doi.dedup.....b37dda1c02bc1d9f5317e7c864025d48