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

Francesca D'Addio, Stefano La Rosa, Anna Maestroni, Peter Jung, Elena Orsenigo, Moufida Ben Nasr, Sara Tezza, Roberto Bassi, Giovanna Finzi, Alessandro Marando, Andrea Vergani, Roberto Frego, Luca Albarello, Annapaola Andolfo, Roberta Manuguerra, Edi Viale, Carlo Staudacher, Domenico Corradi, Eduard Batlle, David BreaultAntonio Secchi, Franco Folli, Paolo Fiorina

Research output: Contribution to journalArticle

Abstract

Summary 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.

Original languageEnglish
Pages (from-to)486-498
Number of pages13
JournalCell Stem Cell
Volume17
Issue number4
DOIs
Publication statusPublished - 2015

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Insulin-Like Growth Factor I
Carrier Proteins
Stem Cells
Type 1 Diabetes Mellitus
Homeostasis
Organoids
Pancreas Transplantation
Somatomedins
Intestinal Mucosa
Recombinant Proteins
Proteomics
Kidney Transplantation
Growth
Serum

Keywords

  • colonic stem cells
  • diabetic enteropathy
  • diabetic nephropathy
  • hyperglycemia
  • IGF-I
  • IGFBP3
  • kidney transplantation
  • pancreas transplantation
  • type 1 diabetes
  • type 2 diabetes
  • uremia

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Medicine
  • Genetics

Cite this

Circulating IGF-I and IGFBP3 Levels Control Human Colonic Stem Cell Function and Are Disrupted in Diabetic Enteropathy. / D'Addio, Francesca; La Rosa, Stefano; Maestroni, Anna; Jung, Peter; Orsenigo, Elena; Ben Nasr, Moufida; Tezza, Sara; Bassi, Roberto; Finzi, Giovanna; Marando, Alessandro; Vergani, Andrea; Frego, Roberto; Albarello, Luca; Andolfo, Annapaola; Manuguerra, Roberta; Viale, Edi; Staudacher, Carlo; Corradi, Domenico; Batlle, Eduard; Breault, David; Secchi, Antonio; Folli, Franco; Fiorina, Paolo.

In: Cell Stem Cell, Vol. 17, No. 4, 2015, p. 486-498.

Research output: Contribution to journalArticle

D'Addio, F, La Rosa, S, Maestroni, A, Jung, P, Orsenigo, E, Ben Nasr, M, Tezza, S, Bassi, R, Finzi, G, Marando, A, Vergani, A, Frego, R, Albarello, L, Andolfo, A, Manuguerra, R, Viale, E, Staudacher, C, Corradi, D, Batlle, E, Breault, D, Secchi, A, Folli, F & Fiorina, P 2015, 'Circulating IGF-I and IGFBP3 Levels Control Human Colonic Stem Cell Function and Are Disrupted in Diabetic Enteropathy', Cell Stem Cell, vol. 17, no. 4, pp. 486-498. https://doi.org/10.1016/j.stem.2015.07.010
D'Addio, Francesca ; La Rosa, Stefano ; Maestroni, Anna ; Jung, Peter ; Orsenigo, Elena ; Ben Nasr, Moufida ; Tezza, Sara ; Bassi, Roberto ; Finzi, Giovanna ; Marando, Alessandro ; Vergani, Andrea ; Frego, Roberto ; Albarello, Luca ; Andolfo, Annapaola ; Manuguerra, Roberta ; Viale, Edi ; Staudacher, Carlo ; Corradi, Domenico ; Batlle, Eduard ; Breault, David ; Secchi, Antonio ; Folli, Franco ; Fiorina, Paolo. / Circulating IGF-I and IGFBP3 Levels Control Human Colonic Stem Cell Function and Are Disrupted in Diabetic Enteropathy. In: Cell Stem Cell. 2015 ; Vol. 17, No. 4. pp. 486-498.
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AU - D'Addio, Francesca

AU - La Rosa, Stefano

AU - Maestroni, Anna

AU - Jung, Peter

AU - Orsenigo, Elena

AU - Ben Nasr, Moufida

AU - Tezza, Sara

AU - Bassi, Roberto

AU - Finzi, Giovanna

AU - Marando, Alessandro

AU - Vergani, Andrea

AU - Frego, Roberto

AU - Albarello, Luca

AU - Andolfo, Annapaola

AU - Manuguerra, Roberta

AU - Viale, Edi

AU - Staudacher, Carlo

AU - Corradi, Domenico

AU - Batlle, Eduard

AU - Breault, David

AU - Secchi, Antonio

AU - Folli, Franco

AU - Fiorina, Paolo

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N2 - Summary 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.

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