The Role of Krüppel-like Factors in Pancreatic Physiology and Pathophysiology

Abstract

Krüppel-like factors (KLFs) belong to the family of transcription factors with three highly conserved zinc finger domains in the C-terminus. They regulate homeostasis, development, and disease progression in many tissues. It has been shown that KLFs play an essential role in the endocrine and exocrine compartments of the pancreas. They are necessary to maintain glucose homeostasis and have been implicated in the development of diabetes. Furthermore, they can be a vital tool in enabling pancreas regeneration and disease modeling. Finally, the KLF family contains proteins that act as tumor suppressors and oncogenes. A subset of members has a biphasic function, being upregulated in the early stages of oncogenesis and stimulating its progression and downregulated in the late stages to allow for tumor dissemination. Here, we describe KLFs' function in pancreatic physiology and pathophysiology.

Keywords: Krüppel-like factors; metabolism; pancreatic cancer; pancreatitis; reprograming; stemness.

Figure 1

The regulatory role of KLFs in β-cell function in the setting of T1D (A,B) and T2D (C–F). (A) Inhibition of KLF2 by miR-92a mediates CXCR5⁺CD4⁺ TFH cells to enrich autoimmune T-cells. (B). Dysregulated KLF4 expression drives M1 macrophage subtype differentiation, in turn, promoting infiltration and inflammation. (C) KLF6 inhibition promotes β-cell de/transdifferentiation to glucagon-secreting α-cells. (D) Enhanced KLF7 expression inhibits transcription of proteins involved in cellular metabolism and insulin secretion. Mutations in KLF11 (E) and KLF14 (F) dysregulate insulin production and secretion and sensitivity/resistance, respectively. Created with BioRender.

Figure 2

Generation of human pancreas-derived stem cells utilizing KLF4 to reprogram cell fate towards pluripotency with the presence of pancreatic cell lineage markers. (A). Colonies with pancreatic stem cell-like morphologies were selected for further experimentation including teratoma potential in mice and PDX1 mRNA expression, a marker of pancreatic stem/progenitor cells. Colonies with no teratoma formation and high relative expression of PDX1 were used for subsequent differentiation protocol to generate induced pancreatic progenitor cells. (B). Stepwise-induced differentiation to functional pancreatic β cells from iTSC-P. Emulation of in vivo embryonic pancreatic development through supplementation of endodermal factors, endocrine precursors, and media shown below each transition arrow. Expression of characteristic genetic markers at each stage of development was measured to ensure pancreatic lineage expression and displayed above respective stage. iPSC: Induced pluripotent stem cell; iTSC-P: Induced tissue-specific stem cell derived from pancreas; GTE: Gut tube endoderm; iTPC: Induced tissue-specific progenitor cells (pancreas-specific). Created with BioRender.

Figure 3

The pattern of KLFs expression during pancreatic carcinogenesis. For details, please see text and Table 1. Created with BioRender.

Figure 4

KLF5 regulates the development of ADM, early pancreatic neoplasia, and low-grade PDAC. (A). Upon injury to the pancreas and/or KRAS activation, KLF5 levels are upregulated, which, in turn, increases Ccnd1, Krt19, and phosphorylation of STAT3. As a result, there is an increase in proliferation of acinar cells and induction of ADM and PanIN formation. (B). In low-grade PDAC, KLF5 positively regulates proliferation, aerobic glycolysis, pyruvate, and lactate production, and reduces apoptosis. Created with BioRender.