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Stem cell based strategies for re-establishing T cell immunity

This article discusses the loss of thymic epithelial cells (TECs) in aging individuals and the negative impact on T cell immunity. It explores potential strategies for re-establishing T cell immunity, including the re-activation of TECs and the generation of TECs from stem cells.

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Stem cell based strategies for re-establishing T cell immunity

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  1. Stem cell based strategies for re-establishing T cell immunity K. Wong, M. Barsanti, M. Hun, A. Alsharif and A. Chidgey Dept Anatomy & Developmental Biology, Monash University, Melbourne Loss of thymic epithelial cells (TEC) underlies age-related immune degeneration: TEC provide most of the specialist functions in the thymus and are critical for the development of self-tolerant T cells and T regulatory cells. From early in life, the thymus gradually atrophies due to a loss in TEC number, precipitating a progressive decline in T cell specificities and immune system function. Most problematic in adults and the elderly, the protracted period of immune deficiency following aggressive cytoablativetreatments associated with cancer therapies and hematopoietic stem cell transplantation, leads to high levels of morbidity and mortality. There are still no effective treatments to improve immune recovery in severely immune-deficient patients. Fig 1A. Numerical loss of immature and mature cortical and medullary TEC subsets in middle aged (9mo) and aged (24mo) mice compared to young (6wk). B. FACS profiles showing proportional loss of immature mTEClo and mature mTEChi cells during aging. Our strategies to re-establish thymus-based de novo generation of a broad based self-tolerant T cell repertoire are: Investigate approaches for endogenous thymic epithelial stem cell (TESC) re-activation; Induce de novo generation of functional human TESCs from pluripotent stem cells; Create ex vivo transplantable thymicorganoids that support the generation of self-tolerant T cells.

  2. 2. Stem cell based strategies for re-establishing T cell immunity We previously identified and characterized TESC in young adult mice (Wong et al, 2014). Using our 3D TEC culture assay, we found reduced colony forming efficiency of adult TESC during ageing, which implicates TESC loss-of-function as a significant mechanism behind the profound loss in lineage specific progenitors and mature epithelial cells. K. Wong, M. Barsanti, M. Hun, A. Alsharif and A. Chidgey Dept Anatomy & Developmental Biology, Monash University, Melbourne Fig 2. Using ourinvitro 3D culture system (left) we found that middle aged TESC generate fewer colonies than young TESC (right). We found Bmp4 to be an important growth factor for TESC self-renewal and maintenance of cortical and medullary lineage specific progenitors (Barsanti/Lim et al, submitted). Fig 3. Addition of Bmp4 to cultures improves TESC colony forming efficiency (left), Foxn1/eGFP expression (middle) and maintenance of cTEClo and mTEClo progenitors (right). Fig 4. The Bmp4 receptor, Bmpr2, is expressed mainly on thymic epithelial stem/progenitor cells and lineage specific progenitors: cTEClo and mTEClo.

  3. 3. Stem cell based strategies for re-establishing T cell immunity To identify further candidate molecules and pathways that could potentially modulate TESC self-renewal, activation and differentiation, we have undertaken a systematic transcriptome analysis of fetal mouse thymus development and adult TECs, spanning thymicprimordium (E9.5; 3rd pharyngeal pouch endoderm), TESC (E10.5 – E11.5), transitioning TESC-TEC (E12.5-13.5) and adult/aged TECs. K. Wong, M. Barsanti, M. Hun, A. Alsharifand A. Chidgey Dept Anatomy & Developmental Biology, Monash University, Melbourne Fig 5.Principal components analyses on (A) gene arrays and (B) microRNA arrays demonstrate consistent grouping of experimental replicates by time points; (C) Pax1 and Foxn1 expression changes over time show expected upregulation from E9.5 and E11.5 respectively. Fig 6. Peak variation was observed at E11.5 with commitment to the thymic epithelial cell lineage. Pre- (E9.5-E10.5) and post- (E12.5-E13.5) thymic commitment stages revealed an inverse transcriptional profile. Molecules that stimulate mTEC generation Molecules that activate TEPCs

  4. 3. Stem cell based strategies for re-establishing T cell immunity Conclusion: Re-establishing a broad spectrum T cell repertoire can potentially be achieved by (1) re-activating endogenous TESC, or (2) generating TESC for transplantation or in vitro T cell differentiation. A thorough understanding of TESC generation in the embryo provides a rational framework to identify target molecules and signaling pathways that may optimise our 3D TESC culture system to support in vitro T cell differentiation, enhance current protocols for in vitro TESC generation from pluripotent stem cells, or induce reactivation of endogenous TESC. K. Wong, M. Barsanti, M. Hun, A. Alsharifand A. Chidgey Dept Anatomy & Developmental Biology, Monash University, Melbourne This work was supported by:

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