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New Developments Towards Thymic Regeneration via Organoid Technology

Review of “Gene modification and 3D scaffolds as novel tools to allow the use of post-natal thymic epithelial cells for thymus regeneration approaches” from STEM CELLS Translational Medicine by Stuart P. Atkinson

Thymic dysfunction renders patients vulnerable to infections, malignancies, and autoimmune diseases [1, 2]; however, stimulating thymic regeneration and thymus transplantation both present with significant problems. The generation of thymic organoids based on three-dimensional cultures of thymic epithelial cells (TECs) may represent a new solution to this problem [3, 4]. Now, a new STEM CELLS Translational Medicine article from laboratory of Marita Bosticardo (IRCCS San Raffaele Scientific Institute, Milan, Italy) reports on the growth of Oct4-“rejuvenated” adult mouse TECs in three-dimensional (3D) biocompatible and biodegradable scaffolds as a new development in the generation of thymic organoids as a step towards thymic regeneration [5].

To obtain transient partial de‐differentiation and promote their expansion, Bortolomai et al. transduced postnatal murine TECs with a lentiviral vector system that allowed for the doxycycline-induced overexpression of the pluripotent stem cell-associated factor Oct4. Encouragingly, Oct4 overexpression allowed expansion without drastically altering cell lineage identity, as evidenced by the retention of important thymus marker gene expression. 

Oct4-overexpressing TECs also grew well in vitro and in vivo within collagen type I scaffolds crosslinked with different amounts of 1,4‐butanediol diglycidyl ether (BDDGE) that reproduced a 3D environment similar to the thymic extracellular matrix. However, while the subcutaneous transplantation of thymic organoids generated using a 3% BDDGE collagen‐based scaffold in athymic nude mice became vascularized, the limited in vivo persistence of the scaffold (degradation observed after two weeks) and its widespread colonization by host neutrophils and macrophages permitted only mild short‐term thymopoietic activity. 

The authors hope that subsequent studies will provide the improvements required to allow long‐term in vivo persistence and thymopoietic activity of thymic organoids through approaches such as employing more substantial numbers of TECs and exploiting alternative biomimetic and functionalized 3D scaffolds. 

For more on thymic organoid generation and all the new developments regarding thymic regeneration, stay tuned to the Stem Cells Portal!

References

  1. Majumdar S and Nandi D, Thymic Atrophy: Experimental Studies and Therapeutic Interventions. Scandinavian Journal of Immunology 2018;87:4-14.
  2. Xiao S, Shterev ID, Zhang W, et al., Sublethal Total Body Irradiation Causes Long-Term Deficits in Thymus Function by Reducing Lymphoid Progenitors. The Journal of Immunology 2017;199:2701.
  3. Poznansky MC, Evans RH, Foxall RB, et al., Efficient generation of human T cells from a tissue-engineered thymic organoid. Nature Biotechnology 2000;18:729-734.
  4. Chung B, Montel-Hagen A, Ge S, et al., Engineering the Human Thymic Microenvironment to Support Thymopoiesis In Vivo. STEM CELLS 2014;32:2386-2396.
  5. Bortolomai I, Sandri M, Draghici E, et al., Gene Modification and Three-Dimensional Scaffolds as Novel Tools to Allow the Use of Postnatal Thymic Epithelial Cells for Thymus Regeneration Approaches. STEM CELLS Translational Medicine 2019;8:1107-1122.