Enhanced BMP Signaling Alters Human β-Cell Identity and Function

Adv Biol (Weinh). 2025 Jan;9(1):e2400470. doi: 10.1002/adbi.202400470. Epub 2024 Nov 5.

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.

Keywords: BMP2; BMP4; diabetes; human pancreatic islets; inflammation.

MeSH terms

  • Bone Morphogenetic Protein 2 / genetics
  • Bone Morphogenetic Protein 2 / metabolism
  • Bone Morphogenetic Protein 4 / metabolism
  • Bone Morphogenetic Proteins / metabolism
  • Endoplasmic Reticulum Stress / drug effects
  • Humans
  • Inflammation / metabolism
  • Insulin-Secreting Cells* / drug effects
  • Insulin-Secreting Cells* / metabolism
  • Interferon-alpha / metabolism
  • Interferon-alpha / pharmacology
  • Interferon-gamma / metabolism
  • Interleukin-1beta / metabolism
  • Signal Transduction* / drug effects
  • Single-Cell Analysis

Substances

  • Bone Morphogenetic Protein 2
  • Interleukin-1beta
  • Bone Morphogenetic Proteins
  • Interferon-gamma
  • Bone Morphogenetic Protein 4
  • Interferon-alpha
  • BMP2 protein, human