Pathways governing development of stem cell‐derived pancreatic β cells: lessons from embryogenesis

Abstract

The loss of functional β cells leads to development of diabetes. Several studies have shown that β cells are specified through several stages of progenitors during pancreas development, each stage defined by the expression of specific transcription factors (TFs). Understanding signalling pathways that control the differentiation and specification processes during embryogenesis will facilitate efforts to obtain functional β cells in vitro. Our current knowledge of the mechanisms involved in pancreatic β cell development and survival under normal or diabetic conditions has come largely from animal studies. However, there are marked differences in islet structure and physiological properties between humans and animals, and not all phenotypes of human diabetes can be recapitulated in animal models. Therefore, human pluripotent stem cells (hPSCs), including human embryonic stem cells (hESCs) and human induced PSCs (hiPSCs) offer a great opportunity for increasing our understanding of the pathways regulating human pancreatic β-cell development and survival. Furthermore, hPSCs provide a renewable source of functional pancreatic β cells for cell replacement therapy as well as disease modelling. Herein, we discuss the signalling pathways involved in the development of pancreatic β cells during embryogenesis. Additionally, we describe how these pathways are manipulated in vitro to differentiate hPSCs into functional β cells. Finally, we highlight the progress that has been made for the applications of those cells in treating and modelling diabetes.

Stem Cell Therapy for Diabetes: Beta Cells versus Pancreatic Progenitors

“…Pancreatic and duodenal homeobox 1 (PDX1) and homeobox protein NKX6.1 (NKX6.1) co-expressing cells within the developing human embryo mark the multipotent pancreatic bud and trunk progenitors that later generate insulin-secreting beta cells [8]. Both key transcription factors (TFs) are highly expressed in pancreatic progenitor cells and functional insulin-secreting beta cells.…”

“…Recent protocols have incorporated TGF beta inhibitors to enhance endocrine cell differentiation [18][19][20][21]. Therefore, in vitro differentiation strategies employ a combination of small molecules or recombinant proteins to turn on or off these pathways at specific stages of the protocol [8,22]. Multiple groups have differentiated hPSCs to PDX1 and NKX6.1 co-expressing pancreatic progenitors in monolayer cultures [16,23], yielding even up to 90% of PDX1+/NKX6.1+ co-positive pancreatic progenitors [24,25] (Figure 3).…”

“…hPSC-derived pancreatic lineage products, with the advantage of being scalable and personalized, are a promising alternative for cell therapy [7]. While step-wise protocols for differentiation of hPSC-derived pancreatic progenitor cells that give rise to mono-hormonal insulin-secreting cells within the body have been designed, in vitro generation of functional pancreatic beta cells has been challenging [8] (Figure 1-2). To date, only one clinical trial has been approved for hPSC-derived product for T1D treatment, led by the company ViaCyte.…”

Tailoring cells for clinical needs: Meeting report from the Advanced Therapy in Healthcare symposium (October 28–29 2017, Doha, Qatar)

“…A clinical trial for diabetic patients treated with human embryonic cells (hESC)-derived pancreatic progenitors macroencapsulated in ENCAPTRA is currently ongoing at San Raffaele Scientific Institute, Italy, in collaboration with Viacyte (US), Brussels University (Belgium), Leiden University (Netherlands) and Nestlè Institute of Health Sciences (Switzerland) ( http://viacyte.com/clinical/clinical-trials/ ). Before transplanting those progenitors, the co-expression of two transcription factors PDX1 and NKX6.1 must be confirmed to assure their differentiation inside the body within few weeks into islet cells [ 97 ]. Recently, Abdelalim’s group was able to establish a highly efficient protocol to generate around 90% of hPSC-derived pancreatic progenitors expressing the key transcription factors (PDX1 + /NKX6.1 + ) required for β-cell maturation [ 98 , 99 ], indicating a dramatic improvement in the differentiation process.…”

“…Furthermore, hPSCs, including hESCs and human induced PSC (hiPSCs) can provide a renewable source of functional pancreatic β-cells to study and treat diabetes, because hPSC-derived β-cells can be closer in nature to the in vivo β-cells than those differentiated from other types of stem cells. hiPSC technology allows to directly generate hPSCs from diabetic patients, providing cells genetically identical to patients to be used for in vitro disease modeling and eventually cell-based therapies [ 97 ]. In Qatar, Abdelalim’s team has generated several hiPSC lines from insulin resistant and diabetic patients, with in vitro differentiation capacity into different cell types including β-cells and insulin-target cells that can be used to understand the pathophysiology of the diabetes.…”