title: Hematopoietic Stem Cells Transplantation Can Normalize Thyroid Function in a Cystinosis Mouse Model.
abstract: Hypothyroidism is the most frequent and earliest endocrine complication in cystinosis, a multisystemic 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 tunneling nanotubes that cross basement laminae. Here we evaluated the benefit of HSC transplantation for cystinotic thyroid and investigated the underlying mechanisms. HSC engraftment in Ctns(-/-) thyroid drastically decreased cystine accumulation, normalized the 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 major histocompatibility complex II but low CD11b and F4/80. Grafted HSCs closely apposed to follicles and produced tunneling nanotube-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 the 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 remanent impact. This is the first report demonstrating the potential of HSC transplantation to correct thyroid disease and supports a major multisystemic benefit of stem cell therapy for cystinosis.
authors.affiliation: Cell Biology Unit (H.P.G.C., V.J., P.V.D.S., C.E.P., P.J.C.), de Duve Institute and Université Catholique de Louvain, 1200 Brussels, Belgium; Department of Pediatrics (C.J.R., S.C.), Division of Genetics, University of California, San Diego, San Diego, California 92161; and Departments of Medicine (X.H.L., S.R.) and Pediatrics and Genetics (S.R.), The University of Chicago, Chicago, Illinois 60637.
authors.forename: H P
authors.initials: HP
authors.lastname: Gaide Chevronnay
authors.affiliation: Cell Biology Unit (H.P.G.C., V.J., P.V.D.S., C.E.P., P.J.C.), de Duve Institute and Université Catholique de Louvain, 1200 Brussels, Belgium; Department of Pediatrics (C.J.R., S.C.), Division of Genetics, University of California, San Diego, San Diego, California 92161; and Departments of Medicine (X.H.L., S.R.) and Pediatrics and Genetics (S.R.), The University of Chicago, Chicago, Illinois 60637.
authors.forename: V
authors.initials: V
authors.lastname: Janssens
authors.affiliation: Cell Biology Unit (H.P.G.C., V.J., P.V.D.S., C.E.P., P.J.C.), de Duve Institute and Université Catholique de Louvain, 1200 Brussels, Belgium; Department of Pediatrics (C.J.R., S.C.), Division of Genetics, University of California, San Diego, San Diego, California 92161; and Departments of Medicine (X.H.L., S.R.) and Pediatrics and Genetics (S.R.), The University of Chicago, Chicago, Illinois 60637.
authors.forename: P
authors.initials: P
authors.lastname: Van Der Smissen
authors.affiliation: Cell Biology Unit (H.P.G.C., V.J., P.V.D.S., C.E.P., P.J.C.), de Duve Institute and Université Catholique de Louvain, 1200 Brussels, Belgium; Department of Pediatrics (C.J.R., S.C.), Division of Genetics, University of California, San Diego, San Diego, California 92161; and Departments of Medicine (X.H.L., S.R.) and Pediatrics and Genetics (S.R.), The University of Chicago, Chicago, Illinois 60637.
authors.forename: C J
authors.initials: CJ
authors.lastname: Rocca
authors.affiliation: Cell Biology Unit (H.P.G.C., V.J., P.V.D.S., C.E.P., P.J.C.), de Duve Institute and Université Catholique de Louvain, 1200 Brussels, Belgium; Department of Pediatrics (C.J.R., S.C.), Division of Genetics, University of California, San Diego, San Diego, California 92161; and Departments of Medicine (X.H.L., S.R.) and Pediatrics and Genetics (S.R.), The University of Chicago, Chicago, Illinois 60637.
authors.forename: X H
authors.initials: XH
authors.lastname: Liao
authors.affiliation: Cell Biology Unit (H.P.G.C., V.J., P.V.D.S., C.E.P., P.J.C.), de Duve Institute and Université Catholique de Louvain, 1200 Brussels, Belgium; Department of Pediatrics (C.J.R., S.C.), Division of Genetics, University of California, San Diego, San Diego, California 92161; and Departments of Medicine (X.H.L., S.R.) and Pediatrics and Genetics (S.R.), The University of Chicago, Chicago, Illinois 60637.
authors.forename: S
authors.initials: S
authors.lastname: Refetoff
authors.affiliation: Cell Biology Unit (H.P.G.C., V.J., P.V.D.S., C.E.P., P.J.C.), de Duve Institute and Université Catholique de Louvain, 1200 Brussels, Belgium; Department of Pediatrics (C.J.R., S.C.), Division of Genetics, University of California, San Diego, San Diego, California 92161; and Departments of Medicine (X.H.L., S.R.) and Pediatrics and Genetics (S.R.), The University of Chicago, Chicago, Illinois 60637.
authors.forename: C E
authors.initials: CE
authors.lastname: Pierreux
authors.affiliation: Cell Biology Unit (H.P.G.C., V.J., P.V.D.S., C.E.P., P.J.C.), de Duve Institute and Université Catholique de Louvain, 1200 Brussels, Belgium; Department of Pediatrics (C.J.R., S.C.), Division of Genetics, University of California, San Diego, San Diego, California 92161; and Departments of Medicine (X.H.L., S.R.) and Pediatrics and Genetics (S.R.), The University of Chicago, Chicago, Illinois 60637.
authors.forename: S
authors.initials: S
authors.lastname: Cherqui
authors.affiliation: Cell Biology Unit (H.P.G.C., V.J., P.V.D.S., C.E.P., P.J.C.), de Duve Institute and Université Catholique de Louvain, 1200 Brussels, Belgium; Department of Pediatrics (C.J.R., S.C.), Division of Genetics, University of California, San Diego, San Diego, California 92161; and Departments of Medicine (X.H.L., S.R.) and Pediatrics and Genetics (S.R.), The University of Chicago, Chicago, Illinois 60637.
authors.forename: P J
authors.initials: PJ
authors.lastname: Courtoy
mesh_terms: D026921:Amino Acid Transport Systems, Neutral / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D003553:Cystine / Q000378:metabolism; D003554:Cystinosis / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D004195:Disease Models, Animal; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D013961:Thyroid Gland / Q000378:metabolism / Q000503:physiopathology*; D013972:Thyrotropin / Q000378:metabolism; D014184:Transplantation, Homologous
chemical_list: D026921:Amino Acid Transport Systems, Neutral; D008164:Luminescent Proteins; C534463:cystinosin protein, mouse; D003553:Cystine; D013972:Thyrotropin
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