Efficient in vitro generation of functional thymic epithelial progenitors from human embryonic stem cells

Su, Min; Hu, Rong; Jin, Jingjun; Yan, Yuan; Song, Yinhong; Sullivan, Ryan P.; Lai, Laijun

doi:10.1038/srep09882

Cited by 39 publications

(33 citation statements)

References 47 publications

(78 reference statements)

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“…Recent work has also demonstrated methods that could be used to drive primitive stem cells into thymic epithelial progenitors cells by precise regulation of crucial factors involved in TEC commitment and maturation, including FOXN1, HOXA3, TGFβ, BMP4, Wnt, Shh, and FGF signaling (187–190), which could be a promising source of cells for a bioengineered thymus. Finally, an innovative alternate approach was taken to generate TECs by direct reprogramming of mouse embryonic fibroblasts (MEFs) through the forced expression of FOXN1 (191).…”

Section: Exogenous Strategies To Enhance Thymic Recoverymentioning

confidence: 99%

“…Although TEPC were identified in the developing thymus almost 15 years ago (182,183), and the presence of an adult progenitor did indeed exist (184), it is only in the past 2 years that significant progress has been made into identifying the postnatal TEPC (185,186). Recent work has also demonstrated methods that could be used to drive primitive stem cells into thymic epithelial progenitors cells by precise regulation of crucial factors involved in TEC commitment and maturation, including FOXN1, HOXA3, TGFb, BMP4, Wnt, Shh, and FGF signaling (187)(188)(189)(190), which could be a promising source of cells for a bioengineered thymus. Finally, an innovative alternate approach was taken to generate TECs by direct reprogramming of mouse embryonic fibroblasts (MEFs) through the forced expression of FOXN1 (191).…”

Section: Thymus Bioengineeringmentioning

confidence: 99%

See 1 more Smart Citation

Thymus: the next (re)generation

Chaudhry

Velardi

Dudakov

et al. 2016

Immunological Reviews

133

131

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Summary As the primary site of T cell development, the thymus plays a key role in the generation of a strong yet self-tolerant adaptive immune response, essential in the face of the potential threat from pathogens or neoplasia. As the importance of the role of the thymus has grown, so too has the understanding that it is extremely sensitive to both acute and chronic injury. The thymus undergoes rapid degeneration following a range of toxic insults, and also involutes as part of the aging process, albeit at a faster rate than many other tissues. The thymus is, however, capable of regenerating, restoring its function to a degree. Potential mechanisms for this endogenous thymic regeneration include keratinocyte growth factor (KGF) signaling, and a more recently described pathway in which innate lymphoid cells produce interleukin-22 (IL-22) in response to loss of double positive thymocytes and upregulation of IL-23 by dendritic cells. Endogenous repair is unable to fully restore the thymus, particularly in the aged population, and this paves the way towards the need for exogenous strategies to help regenerate or even replace thymic function. Therapies currently in clinical trials include KGF, use of the cytokines IL-7 and IL-22, and hormonal modulation including growth hormone administration and sex steroid inhibition. Further novel strategies are emerging in the pre-clinical setting, including the use of precursor T cells and thymus bioengineering. The use of such strategies offers hope that for many patients, the next regeneration of their thymus is a step closer.

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Section: Exogenous Strategies To Enhance Thymic Recoverymentioning

confidence: 99%

Section: Thymus Bioengineeringmentioning

confidence: 99%

Thymus: the next (re)generation

Chaudhry

Velardi

Dudakov

et al. 2016

Immunological Reviews

133

131

View full text Add to dashboard Cite

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“…Therefore, there is great interest in the field to be able to generate high‐quality cells representative of these organs from hPSCs for a myriad of applications. Numerous protocols have described the differentiation of hPSCs toward cells of endodermal origin, including hepatocytes (Hannan, Segeritz, Touboul, & Vallier, ; Hay et al., ; Mathapati et al., ; Siller et al., ; Si‐Tayeb et al., ; Song et al., ; Sullivan et al., ; Touboul et al., ), cholangiocytes (Dianat et al., ; Ogawa et al., ; Sampaziotis et al., ; Yanagida, Ito, Chikada, Nakauchi, & Kamiya, ), pancreatic β cells (Pagliuca et al., ), thymic epithelial cells (Parent et al., ; Su et al., ; Sun et al., ), intestine (Spence et al., ), and lung epithelial cells (Dye et al., ; Huang et al., ).…”

Section: Commentarymentioning

confidence: 99%

Rapid Screening of the Endodermal Differentiation Potential of Human Pluripotent Stem Cells

Siller

Sullivan

2017

CP Stem Cell Biology

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Human pluripotent stem cells (hPSCs) hold tremendous promise for regenerative medicine, disease modeling, toxicology screening, and developmental biology. These applications are hindered due to inherent differences in differentiation potential observed among different hPSC lines. This is particularly true for the differentiation of hPSCs toward the endodermal lineage. Several groups have developed methods to screen hPSCs for their endodermal differentiation potential (EP). Particularly notable studies include (i) the use of WNT3A expression as a predictive biomarker, (ii) an embryoid body-based screen, and (iii) a transcriptomics-based approach. We recently developed a rapid screen to access the EP of hPSCs solely based on morphological analysis. The screen takes 4 days to perform and yields results that are easy to interpret. As the screen is based on our recently developed small molecule protocol for hepatocyte like cell (HLC) differentiation of hPSCs, this method is extremely cost-effective compared to the aforementioned approaches. © 2017 by John Wiley & Sons, Inc.

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“…There are many reports that describe the in vitro production of endodermal cell types from hPSCs: thymic epithelial cells262728, pancreatic beta cells29, lung epithelial cells30, intestinal cells31, cholangiocytes32333435 and hepatocytes35611363738. We recently developed an efficient, small molecule driven method to direct hPSCs to hepatocyte like cells (HLCs)12.…”

mentioning

confidence: 99%

Development of a rapid screen for the endodermal differentiation potential of human pluripotent stem cell lines

Siller

Naumovska

Mathapati

et al. 2016

Sci Rep

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A challenge facing the human pluripotent stem cell (hPSC) field is the variability observed in differentiation potential of hPSCs. Variability can lead to time consuming and costly optimisation to yield the cell type of interest. This is especially relevant for the differentiation of hPSCs towards the endodermal lineages. Endodermal cells have the potential to yield promising new knowledge and therapies for diseases affecting multiple organ systems, including lung, thymus, intestine, pancreas and liver, as well as applications in regenerative medicine and toxicology. Providing a means to rapidly, cheaply and efficiently assess the differentiation potential of multiple hPSCs is of great interest. To this end, we have developed a rapid small molecule based screen to assess the endodermal potential (EP) of hPSCs, based solely on definitive endoderm (DE) morphology. This drastically reduces the cost and time to identify lines suitable for use in deriving endodermal lineages. We demonstrate the efficacy of this screen using 10 different hPSCs, including 4 human embryonic stem cell lines (hESCs) and 6 human induced pluripotent stem cell lines (hiPSCs). The screen clearly revealed lines amenable to endodermal differentiation, and only lines that passed our morphological assessment were capable of further differentiation to hepatocyte like cells (HLCs).

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Efficient in vitro generation of functional thymic epithelial progenitors from human embryonic stem cells

Cited by 39 publications

References 47 publications

Thymus: the next (re)generation

Thymus: the next (re)generation

Rapid Screening of the Endodermal Differentiation Potential of Human Pluripotent Stem Cells

Development of a rapid screen for the endodermal differentiation potential of human pluripotent stem cell lines

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