title: Pluripotent stem cell models of Shwachman-Diamond syndrome reveal a common mechanism for pancreatic and hematopoietic dysfunction.
abstract: Shwachman-Diamond syndrome (SDS), a rare autosomal-recessive disorder characterized by exocrine pancreatic insufficiency and hematopoietic dysfunction, is caused by mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene. We created human pluripotent stem cell models of SDS through knockdown of SBDS in human embryonic stem cells (hESCs) and generation of induced pluripotent stem cell (iPSC) lines from two patients with SDS. SBDS-deficient hESCs and iPSCs manifest deficits in exocrine pancreatic and hematopoietic differentiation in vitro, enhanced apoptosis, and elevated protease levels in culture supernatants, which could be reversed by restoring SBDS protein expression through transgene rescue or by supplementing culture media with protease inhibitors. Protease-mediated autodigestion provides a mechanistic link between the pancreatic and hematopoietic phenotypes in SDS, highlighting the utility of hESCs and iPSCs in obtaining novel insights into human disease.
authors.affiliation: Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Asmin
authors.initials: A
authors.lastname: Tulpule
authors.forename: James M
authors.initials: JM
authors.lastname: Kelley
authors.forename: M William
authors.initials: MW
authors.lastname: Lensch
authors.forename: Jade
authors.initials: J
authors.lastname: McPherson
authors.forename: In Hyun
authors.initials: IH
authors.lastname: Park
authors.forename: Odelya
authors.initials: O
authors.lastname: Hartung
authors.forename: Tomoka
authors.initials: T
authors.lastname: Nakamura
authors.forename: Thorsten M
authors.initials: TM
authors.lastname: Schlaeger
authors.forename: Akiko
authors.initials: A
authors.lastname: Shimamura
authors.forename: George Q
authors.initials: GQ
authors.lastname: Daley
mesh_terms: D001855:Bone Marrow Diseases / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D010188:Exocrine Pancreatic Insufficiency / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology*; D006412:Hematopoietic Stem Cells / Q000201:enzymology / Q000473:pathology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000201:enzymology / Q000473:pathology*; D008068:Lipomatosis / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology*; D008954:Models, Biological; D010179:Pancreas / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology*; D010447:Peptide Hydrolases / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D000081003:Shwachman-Diamond Syndrome
chemical_list: D011480:Protease Inhibitors; D010447:Peptide Hydrolases