Table 1.

Promising strategies for pancreatic β-cell regeneration.

Cell types	Instructive strategies	Advantages	Limitations and challenges	Functioning validity (weeks)	Involved mechanisms	Refs
Pancreatic non-β-cells
Acinar cells	Injury (PDL, PPX); Transduction of pancreatic transcription factors MafA, PDX1 and Ngn3/ NeuroD1; Administration of cytokines EGF, CNTF, nicotinamide, LIF; Peptide (GLP-1)	Similar developmental background to β-cells in vivo; Large proportion and flexible plasticity; Share quantity of transcription factors; Corresponding metabolic mechanism and hormone secretion	Low conversion rate; Weak proliferative capacity and stability; Immature morphology and biological function; The reprogramming effectiveness and efficiency with or without gene manipulation need to be improved	2	PI3K/Akt pathways; MAPK/STAT3 signaling pathways; Erk1/2 signaling pathways	(101, 111, 112, 113)
Duct cells	Injury (PDL, PPX); Ectopic overexpression of MafA, PDX1 and Ngn3/ NeuroD1, Pax6 needed for human ductal reprogramming; Administration of cytokines TGFα, DNA methyltransferase inhibitor; Peptide (GLP-1, gastrin)			5–12		(100, 107, 114, 115)
α and δ cells	Almost complete ablation of β-cells (PDL, PPX, diphtheria toxin); Overexpression of Pdx1, PAX4, MafA; Suppression of Arx; Peptides (GLP-1, GABA, artemisinin)			4–16		(98, 99, 102, 103, 104, 108, 109, 110)
Liver cells	Ectopically overexpressing PDX1 and NeuroD1; Down-regulating the expression of HNF1α and HNF4α; Specific factors (GLP-1R, Notch inhibitors, TGF-β inhibitors)	Conveniently accessible; Sufficient source and cultivate easily; Great regeneration and conversion ability; Share common characteristics including responsiveness to glucose, and mass of specific transcription factors	Efficient viral transfection strategies accompanied with safety concerns; Exploring cytokine or chemical induced safe and effective transition is prospective	4–8	Wnt signaling pathway	(119, 120, 121)
Biliary cells	Transduction of pancreatic transcription factors Pdx1, NeuroD1, Ngn3, MafA or Pdx1/VP16; Excision of Hes1	Conveniently accessible	Limited source of cells; Transient transformation; Expand cell source and optimize reprogramming protocol need to be investigated	3–4	Notch signaling pathway	(122, 123, 124, 125)
Gastrointestinal cells
Intestinal cells	Ectopic expression of Pdx1, MafA, and Ngn3; Excision of transcription factor FoxO1; Peptide (GLP-1); ‘Small intestinal organ’	Simple, non-invasive, easy to access; Sufficient source and cultivate easily; Great regeneration and conversion ability; Similar glucose sensitive system and secretion mechanism with islet cells	Low conversion rate	1–3	PI3K/Akt/FoxO1 pathways	(126, 128, 129)
Glandular cells	Ectopic expression of Pdx1, MafA, and Ngn3; ‘Stomach mini-organs’			3–6		(134, 136, 138)