Towards a Patient-Specific Stem Cell Treatment for Thyroid Loss -

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Towards a Patient-Specific Stem Cell Treatment for Thyroid Loss4 |) E; O5 k6 V! N) f" U; f# A
See more at: http://www.stemcellsportal.com/t ... atment-thyroid-loss6 x" ]+ Y& g' g8 Z
December 28, 2015
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# l$ M# T; @* jReview of “Regeneration of Thyroid Function by Transplantation of Differentiated Pluripotent Stem Cells” from Cell Stem Cell by Stuart P. Atkinson9 J. ?, j# c& X4 ^/ r+ b- _- }( Y
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While the directed differentiation of human pluripotent stem cells (hPSCs) as three-dimensional organoids has proven successful for many organs, our knowledge regarding thyroid differentiation is currently lacking. To rectify this problem, researchers from the laboratory of Darrell N. Kotton sought to investigate the pathways involved and the potential for functional thyroid tissue growth. Their new study, published in Cell Stem Cell, describes how BMP4 and FGF2 signaling are key for thyroid specification, and demonstrate the production of thyroid follicular cells that produce thyroid hormones and rescue hypothyroidism in mice. Additionally, the show that stimulation of the same pathways can produce human thyroid progenitors from normal and disease-specific iPSCs [1].9 M7 z  Z; ~" r+ `( ~2 {& {3 I/ W+ e) D

9 W' Z' F" L7 ~" [5 f  xPrevious studies which attained functional thyroid epithelial cells used forced overexpression of transcription factors [2-4], a strategy that this new paper avoided to promote the clinical relevancy of their study. Instead, the group applied a modified serum-free, feeder-free differentiation protocol in conditions used to produce definitive endodermal cells [5]. They discovered that the promotion of Bmp4 and Fgf2 signaling produced a small population of endodermal cells which expressed two important thyroid makers (Nkx2-1 and Pax8), so suggesting them to be thyroid progenitor cells.
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The addition of thyroid-stimulating hormone (TSH) and dexamethasone to these cells mediated their maturation into thyroid cells expressing high levels of genes required for iodine metabolism and thyroid hormone biosynthesis. When these cells were grown in 3D conditions, thyroid-associated gene expression increased and triggered the formation of thyroid follicle-like clusters of cells (or organoids) with a thyroid-like structure, gene expression pattern, and functional output, (ability to organify iodine and produce hormones). ( D2 F- V% V! j8 I: G
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To fully test the functionality of the thyroid organoids, the researchers assessed whether or not they could synthesize and secrete thyroid hormones following transplantation beneath the left kidney capsule of mouse recipients lacking a functional thyroid gland. Transplanted organoids retained their structure, retained their phenotype, mediated the long-term expression of thyroid hormones, were regulated by TSH expression, and showed no signs of teratoma formation.3 e! N! ^1 V1 K

# D. f: n' L$ _- FSuccess! We now have the ability to differentiate PSCs into thyroid progenitors which can then be used to generate functional thyroid tissue in mice. The group was also able to generate human thyroid progenitors from both hESCs and induced pluripotent stem cells (iPSCs) generated from fibroblasts from hypothyroid children caused by NKX2-1 coding sequence mutations. These cells expressed thyroid-associated genes as hoped and, hopefully, the next step in this search will be to investigate the potential of hPSC-derived thyroid organoids toward a safe and effective patient-specific treatment for thyroid loss.2 ]3 N" D# E7 ^2 ^' K9 c

4 p7 P" f4 ?) ^# ^7 |- See more at: http://www.stemcellsportal.com/t ... thash.kdLqSxih.dpuf5 r# }( h; E0 Y* \- G

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$ L" b& L' @- y$ X: aPatient-specific thyroid cells generated in the lab. ~( c# n3 Y# n2 h- a3 f  s. v

0 t  G0 h7 ~9 i  \* L* kDeveloped thyroid cells in a unit called a follicle
) J3 y5 N8 p0 gDeveloped thyroid cells in a unit called a follicle. The pink stain is thyroglobulin, which is a precursor of thyroid hormone0 G* O/ ?4 H) F5 k( A1 r
Credit: Anita Kurmann and Maria Serra; a0 @6 W3 N" ^$ E+ |

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22 October 2015
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As stem cell researchers make progress in regenerative therapies for the eye, heart, and brain, those working on a less studied part of the anatomy, the thyroid gland, have quietly been amassing the biological knowledge of thyroid development needed to make a leap of their own. In a study published in Cell Stem Cell, Boston-led researchers present the first stem-cell-derived human thyroid tissue generated from both normal individuals and patients with hypothyroidism.
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9 M& @6 d$ B( jPrevious work in the field had demonstrated that mouse thyroid cells could be generated from embryonic stem cells but only by artificially over-expressing key thyroid-specific genes. “We found this process could be recapitulated in a laboratory dish by adding a sequence of proteins called growth factors to the fluid bathing the stem cells,” says co-senior author Darrell Kotton of the Center for Regenerative Medicine of Boston University and Boston Medical Center.
) l0 k0 A/ G$ M, ?% RThe investigators tested their method – which relied mainly on the growth factors FGF2 and BMP4 – with mouse pluripotent stem cells, which were then used to regenerate thyroid function after transplantation in a mouse model of hypothyroidism. The team then adapted the method to produce thyroid cells using induced pluripotent stem cells generated from children who had genetic defects that had caused them to have an underactive thyroid.
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( b8 X- r# r0 u6 G/ \“Hypothyroidism is common in adults and also affects children born with congenital or inherited forms of thyroid disease,” says co-senior author Anthony Hollenberg of Beth Israel Deaconess Medical Center. “Although there are good drugs available to replace thyroid function, we can now envision that children or adults may one day be able to receive sustained rescue of their thyroid function by transplanting their own thyroid cells regenerated in the laboratory from cells made by reprogramming their skin or blood cells.”
* ^$ b1 r( b! l% Bfrom:http://internetmedicine.com/2015/10/23/44631/
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