Loss of Human Beta Cell Identity in a Reconstructed Omental Stromal Cell Environment.

Blandine Secco,Nicolas Venteclef,Kevin Saitoski,Antoine Soprani,Karima Drareni,Severine Pechberty,Latif Rachdi,Raphaël Scharfmann

doi:10.3390/cells11060924

Abstract

In human type 2 diabetes, adipose tissue plays an important role in disturbing glucose homeostasis by secreting factors that affect the function of cells and tissues throughout the body, including insulin-producing pancreatic beta cells. We aimed here at studying the paracrine effect of stromal cells isolated from subcutaneous and omental adipose tissue on human beta cells. We developed an in vitro model wherein the functional human beta cell line EndoC-βH1 was treated with conditioned media from human adipose tissues. By using RNA-sequencing and western blotting, we determined that a conditioned medium derived from omental stromal cells stimulates several pathways, such as STAT, SMAD and RELA, in EndoC-βH1 cells. We also observed that upon treatment, the expression of beta cell markers decreased while dedifferentiation markers increased. Loss-of-function experiments that efficiently blocked specific signaling pathways did not reverse dedifferentiation, suggesting the implication of more than one pathway in this regulatory process. Taken together, we demonstrate that soluble factors derived from stromal cells isolated from human omental adipose tissue signal human beta cells and modulate their identity.

Highlights

The endocrine pancreas plays a crucial role in nutritional homeostasis through the synthesis and secretion of hormones by cells aggregated into islets of Langerhans
Around 1000 genes were differently expressed between the control conditions and treatment with Conditioned Media (CM) by the stromal cells (1157 and 878 when stromal cells were pretreated or not with TNF-α respectively), and 141 genes were deregulated in EndoC-βH1 pretreated with CM from stromal cells differentiated into adipocytes
We observed that CMs from human omental stromal cells gives rise to an inflammatory signature in EndoC-βH1 cells

Summary

Introduction

The islets of Langerhans are endocrine micro-organs implicated in glycemic regulation They are dispersed in the pancreatic gland. While it has been proposed that the beta cell mass decreases in T2D patients due to premature programmed cell death [9,10], recent data challenge the beta cell death hypothesis They suggest that beta cell dedifferentiation represents an alternative mechanism to explain the insufficient insulin production observed in type 2 diabetes [11,12]. This concept is supported by experiments performed in a number of experimental models [13–15]. We previously developed functional human beta cells lines [18,19] and used them to model human beta cell dedifferentiation under pathophysiological conditions [20,21]

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Conclusion