Enhanced BMP Signaling Alters Human β‐Cell Identity and Function

Advanced Biology, vol. 9, pp. e2400470

Abstract

Inflammation contributes to the pathophysiology of diabetes. Identifying signaling pathways involved in pancreatic β-cell failure and identity loss can give insight into novel potential treatment strategies to prevent the loss of functional β-cell mass in diabetes. It is reported earlier that the immunosuppressive drug tacrolimus has a detrimental effect on human β-cell identity and function by activating bone morphogenetic protein (BMP) signaling. Here it is hypothesized that enhanced BMP signaling plays a role in inflammation-induced β-cell failure. Single-cell transcriptomics analyses of primary human islets reveal that IL-1β+IFNγ and IFNα treatment activated BMP signaling in β-cells. These findings are validated by qPCR. Furthermore, enhanced BMP signaling with recombinant BMP2 or 4 triggers a reduced expression of key β-cell maturity genes, associated with increased ER stress, and impaired β-cell function. Altogether, these results indicate that inflammation-activated BMP signaling is detrimental to pancreatic β-cells and that BMP-signaling can be a target to preserve β-cell identity and function in a pro-inflammatory environment.

Authors 5

1. Javier Triñanes Aachen Department of Internal Medicine

   Leiden University Medical Center

   Affiliation as printed

   Department of Internal Medicine Leiden University Medical Center Albinusdreef 2 Leiden 2333 ZA The Netherlands

   Department of Internal Medicine, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333 ZA The Netherlands

2. Amadeo Munoz-Garcia Aachen Department of Internal Medicine

   Leiden University Medical Center

   Affiliation as printed

   Department of Internal Medicine Leiden University Medical Center Albinusdreef 2 Leiden 2333 ZA The Netherlands

   Department of Internal Medicine, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333 ZA The Netherlands

3. Natascha de Graaf Aachen Department of Internal Medicine

   Leiden University Medical Center

   Affiliation as printed

   Department of Internal Medicine Leiden University Medical Center Albinusdreef 2 Leiden 2333 ZA The Netherlands

   Department of Internal Medicine, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333 ZA The Netherlands

4. Eelco J.P. de Koning Aachen Department of Internal Medicine

   Leiden University Medical Center

   Affiliation as printed

   Department of Internal Medicine Leiden University Medical Center Albinusdreef 2 Leiden 2333 ZA The Netherlands

   Department of Internal Medicine, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333 ZA The Netherlands

5. Françoise Carlotti corresponding Aachen Department of Internal Medicine

   Leiden University Medical Center

   Affiliation as printed

   Department of Internal Medicine Leiden University Medical Center Albinusdreef 2 Leiden 2333 ZA The Netherlands

   Department of Internal Medicine, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333 ZA The Netherlands