title: Regeneration in the Pituitary After Cell-Ablation Injury: Time-Related Aspects and Molecular Analysis.
abstract: We recently showed that the mouse pituitary holds regenerative competence. Young-adult GHCre/iDTR mice, expressing diphtheria toxin (DT) receptor in GH-producing cells, regenerate the GH(+) cells, as ablated by 3-day DT treatment (3DT), up to 60% after 5 months. The pituitary's stem cells participate in this restoration process. Here, we characterized this regenerative capacity in relation to age and recovery period and started to search for underlying molecular mechanisms. Extending the recovery period (up to 19 mo) does not result in higher regeneration levels. In addition, the regenerative competence disappears at older age, coinciding with a reduction in pituitary stem cell number and fitness. Surprisingly, prolonging DT treatment of young-adult mice to 10 days (10DT) completely blocks the regeneration, although the stem cell compartment still reacts by promptly expanding, and retains in vitro stem cell functionality. To obtain a first broad view on molecular grounds underlying reparative capacity and/or failure, the stem cell-clustering side population was analyzed by whole-genome expression analysis. A number of stemness factors and components of embryonic, epithelial-mesenchymal transition, growth factor and Hippo pathways are higher expressed in the stem cell-clustering side population of the regenerating pituitary (after 3DT) when compared with the basal gland and to the nonregenerating pituitary (after 10DT). Together, the regenerative capacity of the pituitary is limited both in age-related terms and final efficacy, and appears to rely on stem cell-associated pathway activation. Dissection of the molecular profiles may eventually identify targets to induce or boost regeneration in situations of (injury-related) pituitary deficiency.
authors.affiliation: Department of Development and Regeneration (C.W., Q.F., H.R., F.M., B.C., J.C., H.V.), Cluster Stem Cell Biology and Embryology, Unit of Stem Cell Research, University of Leuven (KU Leuven), Leuven 3000, Belgium; Eye Center (Q.F.), Second Affiliated Hospital, School of Medicine, Zhejiang University, and Key Laboratory of Ophthalmology of Zhejiang Province, Hangzhou 310009, China; and Department of Hand Surgery (J.C.), Tongji Medical College, Union Hospital, Huazhong University of Science and Technology (HUST), Wuhan, Hubei 430022, China.
authors.forename: Christophe
authors.initials: C
authors.lastname: Willems
authors.affiliation: Department of Development and Regeneration (C.W., Q.F., H.R., F.M., B.C., J.C., H.V.), Cluster Stem Cell Biology and Embryology, Unit of Stem Cell Research, University of Leuven (KU Leuven), Leuven 3000, Belgium; Eye Center (Q.F.), Second Affiliated Hospital, School of Medicine, Zhejiang University, and Key Laboratory of Ophthalmology of Zhejiang Province, Hangzhou 310009, China; and Department of Hand Surgery (J.C.), Tongji Medical College, Union Hospital, Huazhong University of Science and Technology (HUST), Wuhan, Hubei 430022, China.
authors.forename: Qiuli
authors.initials: Q
authors.lastname: Fu
authors.affiliation: Department of Development and Regeneration (C.W., Q.F., H.R., F.M., B.C., J.C., H.V.), Cluster Stem Cell Biology and Embryology, Unit of Stem Cell Research, University of Leuven (KU Leuven), Leuven 3000, Belgium; Eye Center (Q.F.), Second Affiliated Hospital, School of Medicine, Zhejiang University, and Key Laboratory of Ophthalmology of Zhejiang Province, Hangzhou 310009, China; and Department of Hand Surgery (J.C.), Tongji Medical College, Union Hospital, Huazhong University of Science and Technology (HUST), Wuhan, Hubei 430022, China.
authors.forename: Heleen
authors.initials: H
authors.lastname: Roose
authors.affiliation: Department of Development and Regeneration (C.W., Q.F., H.R., F.M., B.C., J.C., H.V.), Cluster Stem Cell Biology and Embryology, Unit of Stem Cell Research, University of Leuven (KU Leuven), Leuven 3000, Belgium; Eye Center (Q.F.), Second Affiliated Hospital, School of Medicine, Zhejiang University, and Key Laboratory of Ophthalmology of Zhejiang Province, Hangzhou 310009, China; and Department of Hand Surgery (J.C.), Tongji Medical College, Union Hospital, Huazhong University of Science and Technology (HUST), Wuhan, Hubei 430022, China.
authors.forename: Freya
authors.initials: F
authors.lastname: Mertens
authors.affiliation: Department of Development and Regeneration (C.W., Q.F., H.R., F.M., B.C., J.C., H.V.), Cluster Stem Cell Biology and Embryology, Unit of Stem Cell Research, University of Leuven (KU Leuven), Leuven 3000, Belgium; Eye Center (Q.F.), Second Affiliated Hospital, School of Medicine, Zhejiang University, and Key Laboratory of Ophthalmology of Zhejiang Province, Hangzhou 310009, China; and Department of Hand Surgery (J.C.), Tongji Medical College, Union Hospital, Huazhong University of Science and Technology (HUST), Wuhan, Hubei 430022, China.
authors.forename: Benoit
authors.initials: B
authors.lastname: Cox
authors.affiliation: Department of Development and Regeneration (C.W., Q.F., H.R., F.M., B.C., J.C., H.V.), Cluster Stem Cell Biology and Embryology, Unit of Stem Cell Research, University of Leuven (KU Leuven), Leuven 3000, Belgium; Eye Center (Q.F.), Second Affiliated Hospital, School of Medicine, Zhejiang University, and Key Laboratory of Ophthalmology of Zhejiang Province, Hangzhou 310009, China; and Department of Hand Surgery (J.C.), Tongji Medical College, Union Hospital, Huazhong University of Science and Technology (HUST), Wuhan, Hubei 430022, China.
authors.forename: Jianghai
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Development and Regeneration (C.W., Q.F., H.R., F.M., B.C., J.C., H.V.), Cluster Stem Cell Biology and Embryology, Unit of Stem Cell Research, University of Leuven (KU Leuven), Leuven 3000, Belgium; Eye Center (Q.F.), Second Affiliated Hospital, School of Medicine, Zhejiang University, and Key Laboratory of Ophthalmology of Zhejiang Province, Hangzhou 310009, China; and Department of Hand Surgery (J.C.), Tongji Medical College, Union Hospital, Huazhong University of Science and Technology (HUST), Wuhan, Hubei 430022, China.
authors.forename: Hugo
authors.initials: H
authors.lastname: Vankelecom
mesh_terms: D000367:Age Factors; D000818:Animals; D004167:Diphtheria Toxin / Q000633:toxicity*; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D066257:Heparin-binding EGF-like Growth Factor / Q000819:agonists* / Q000235:genetics; D000090683:Hippo Signaling Pathway; D007018:Hypopituitarism / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010902:Pituitary Gland / Q000293:injuries / Q000378:metabolism / Q000502:physiology; D010903:Pituitary Gland, Anterior / Q000293:injuries / Q000378:metabolism* / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D020127:Recovery of Function; D012038:Regeneration / Q000235:genetics* / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D052683:Somatotrophs / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism*; D013997:Time Factors
chemical_list: D004167:Diphtheria Toxin; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D017346:Protein Serine-Threonine Kinases