Circulating IGF-I and IGFBP3 Levels Control Human Colonic Stem Cell Function and Are Disrupted in Diabetic Enteropathy

被引：72

作者：

D'Addio, Francesca ^{[1
,2
]}

La Rosa, Stefano ^{[3
]}

Maestroni, Anna ^{[2
]}

Jung, Peter ^{[4
]}

Orsenigo, Elena ^{[5
]}

Ben Nasr, Moufida ^{[1
,2
]}

Tezza, Sara ^{[1
,2
]}

Bassi, Roberto ^{[1
,2
]}

Finzi, Giovanna ^{[3
]}

Marando, Alessandro ^{[3
]}

Vergani, Andrea ^{[1
,2
]}

Frego, Roberto ^{[6
]}

Albarello, Luca ^{[7
]}

Andolfo, Annapaola ^{[8
]}

Manuguerra, Roberta ^{[9
]}

Viale, Edi ^{[6
]}

Staudacher, Carlo ^{[5
]}

Corradi, Domenico ^{[9
]}

Batlle, Eduard ^{[4
,10
]}

Breault, David ^{[11
]}

Secchi, Antonio ^{[2
,12
]}

Folli, Franco ^{[13
,14
]}

Fiorina, Paolo ^{[1
,2
]}

机构：

[1] Harvard Univ, Sch Med, Div Nephrol, Boston Childrens Hosp, Boston, MA 02115 USA

[2] IRCCS, Osped San Raffaele, Transplant Med, I-20132 Milan, Italy

[3] Osped Circolo Varese, Dept Pathol, I-21100 Varese, Italy

[4] IRB Barcelona, Barcelona 08028, Spain

[5] IRCCS, Osped San Raffaele, Surg, I-20132 Milan, Italy

[6] IRCCS, Osped San Raffaele, Gastroenterol, I-20132 Milan, Italy

[7] IRCCS, Osped San Raffaele, Pathol Unit, I-20132 Milan, Italy

[8] IRCCS, Osped San Raffaele, ProMiFa, Prot Microsequencing Facil, I-20132 Milan, Italy

[9] Univ Parma, Dept Biomed Biotechnol & Translat Sci, Unit Pathol, I-43121 Parma, Italy

[10] ICREA, Barcelona 08028, Spain

[11] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA

[12] Univ Vita Salute San Raffaele, I-20132 Milan, Italy

[13] Univ Texas Hlth Sci Ctr San Antonio, Div Diabet, Dept Med, San Antonio, TX 78229 USA

[14] Univ Estadual Campinas, OCRC, Dept Internal Med, BR-13100 Sao Paulo, Brazil

来源：

CELL STEM CELL | 2015年 / 17卷 / 04期

基金：

巴西圣保罗研究基金会;

关键词：

STAGE RENAL-DISEASE; GASTROINTESTINAL SYMPTOMS; NATURAL-HISTORY; INSULIN; PANCREAS; MELLITUS; TRANSPLANTATION; EXPRESSION; EXPANSION; IMPACT;

D O I：

10.1016/j.stem.2015.07.010

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

The role of circulating factors in regulating colonic stem cells (CoSCs) and colonic epithelial homeostasis is unclear. Individuals with long-standing type 1 diabetes (T1D) frequently have intestinal symptoms, termed diabetic enteropathy (DE), though its etiology is unknown. Here, we report that T1D patients with DE exhibit abnormalities in their intestinal mucosa and CoSCs, which fail to generate in vitro mini-guts. Proteomic profiling of T1D+DE patient serum revealed altered levels of insulin-like growth factor 1 (IGF-I) and its binding protein 3 (IGFBP3). IGFBP3 prevented in vitro growth of patient-derived organoids via binding its receptor TMEM219, in an IGF-I-independent manner, and disrupted in vivo CoSC function in a preclinical DE model. Restoration of normoglycemia in patients with long-standing T1D via kidney-pancreas transplantation or in diabetic mice by treatment with an ecto-TMEM219 recombinant protein normalized circulating IGF-I/IGFBP3 levels and reestablished CoSC homeostasis. These findings demonstrate that peripheral IGF-I/IGFBP3 controls CoSCs and their dysfunction in DE.

引用

页码：486 / 498

页数：13

共 44 条

[1]

[Anonymous], LANCET

[2] Type 1 diabetes [J].