title: Bile Acids Protect Expanding Hematopoietic Stem Cells from Unfolded Protein Stress in Fetal Liver.
abstract: During development, hematopoietic stem cells (HSCs) undergo a rapid expansion in the fetal liver (FL) before settling in the adult bone marrow. We recently reported that proliferating adult HSCs are vulnerable to ER stress caused by accumulation of mis-folded proteins. Here, we find that FL-HSCs, despite an increased protein synthesis rate and a requirement for protein folding, do not upregulate ER chaperones. Instead, bile acids (BAs), secreted from maternal and fetal liver, coordinate to serve as chemical chaperones. Taurocholic acid, the major BA in FL, supports growth of HSCs in vitro by inhibiting protein aggregation. In vivo, reducing BA levels leads to ER stress elevation and accumulation of aggregated proteins and significantly decreases the number of FL-HSCs. Taken together, these findings reveal that BA alleviation of ER stress is a mechanism required for HSC expansion during fetal hematopoiesis.
authors.affiliation: Division of Molecular Medicine and Gene Therapy, Lund Strategic Center for Stem Cell Biology, Lund University, 221 84 Lund, Sweden.
authors.forename: Valgardur
authors.initials: V
authors.lastname: Sigurdsson
authors.affiliation: Junshin Clinic Bile Acid Institute, 152-0011 Tokyo, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Takei
authors.affiliation: Division of Molecular Medicine and Gene Therapy, Lund Strategic Center for Stem Cell Biology, Lund University, 221 84 Lund, Sweden.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Soboleva
authors.affiliation: Division of Molecular Medicine and Gene Therapy, Lund Strategic Center for Stem Cell Biology, Lund University, 221 84 Lund, Sweden.
authors.forename: Visnja
authors.initials: V
authors.lastname: Radulovic
authors.affiliation: Division of Molecular Medicine and Gene Therapy, Lund Strategic Center for Stem Cell Biology, Lund University, 221 84 Lund, Sweden.
authors.forename: Roman
authors.initials: R
authors.lastname: Galeev
authors.affiliation: Division of Molecular Medicine and Gene Therapy, Lund Strategic Center for Stem Cell Biology, Lund University, 221 84 Lund, Sweden.
authors.forename: Kavitha
authors.initials: K
authors.lastname: Siva
authors.affiliation: Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden.
authors.forename: L M Fredrik
authors.initials: LM
authors.lastname: Leeb-Lundberg
authors.affiliation: Department of Chemistry, College of Humanities and Sciences, Nihon University, 156-8550 Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Iida
authors.affiliation: Junshin Clinic Bile Acid Institute, 152-0011 Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nittono
authors.affiliation: Division of Molecular Medicine and Gene Therapy, Lund Strategic Center for Stem Cell Biology, Lund University, 221 84 Lund, Sweden. Electronic address: kenichi.miharada@med.lu.se.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Miharada
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000494:pharmacology*; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects; D011247:Pregnancy; D011270:Pregnancy, Animal; D066329:Protein Aggregates / Q000187:drug effects; D056811:Unfolded Protein Response / Q000187:drug effects*
chemical_list: D001647:Bile Acids and Salts; D066329:Protein Aggregates