Hematopoietic stem cells transplantation can normalize thyroid function in a cystinosis mouse model.

Hypothyroidism is the most frequent and earliest endocrine complication in cystinosis, a multi-systemic lysosomal storage disease caused by defective transmembrane cystine transporter, cystinosin (CTNS gene). We recently demonstrated in Ctns(-/-) mice that altered thyroglobulin biosynthesis associated with endoplasmic reticulum stress, combined with defective lysosomal processing, caused hypothyroidism. In Ctns(-/-) kidney, hematopoietic stem cell (HSC) transplantation provides long-term functional and structural protection. Tissue repair involves transfer of cystinosin-bearing lysosomes from HSCs differentiated as F4/80 macrophages into deficient kidney tubular cells, via tunnelling nanotubes (TNTs) that cross basement laminae. Here, we evaluated the benefit of HSCs transplantation for cystinotic thyroid and investigated underlying mechanisms. HSC engraftment in Ctns(-/-) thyroid drastically decreased cystine accumulation, normalized TSH level and corrected the structure of a large fraction of thyrocytes. In the thyroid microenvironment, HSCs differentiated into a distinct, mixed macrophage/dendritic cell lineage expressing CD45 and MHCII but low CD11b and F4/80. Grafted HSCs closely apposed to follicles and produced TNT-like extensions that crossed follicular basement laminae. HSCs themselves further squeezed into follicles, allowing extensive contact with thyrocytes, but did not transdifferentiate into Nkx2.1-expressing cells. Our observations revealed significant differences of basement lamina porosity between thyroid and kidney, and/or intrinsic macrophage invasive properties once in the thyroid microenvironment. The contrast between extensive thyrocyte protection and low HSC abundance at steady state suggests multiple sequential encounters and/or remnant impact. This is the first report demonstrating the potential of HSCs transplantation to correct thyroid disease, and supports a major multisystemic benefit of stem cells therapy for cystinosis