Table 1.

Summary of some novel signaling pathways perturbed during pancreatic differentiation of hPSCs.

	Molecules	Mechanism	Induction of pancreatic lineage markers	Reference	Humans	Rodents
TGF-β inhibition	SB431542	Inhibits ALK 4/5/7	Upregulates INS gene expression and C-peptide+ cells	Nostro et al. (15)	√
	SB431542 + RA		Upregulates PDX1 gene expression	Cho et al. (16)	√
	TGF-βRI kinase inhibitor IV		Induces pancreatic progenitors from hPSCs	Schultz et al. (17)	√
	1 μM ALK5iII	Inhibits ALK5	Downregulates NGN3. Upregulates NEUROD, INS, GCG, and SST transcripts Induces Mafa transcript expression in diabetic rodents	Rezania et al. (4, 6, 18)	√	√
	10 μM ALK5iII			Pagliuca et al. (7)	√
Protein kinase C signaling	300 nM ILV	Activates PKC Synergizes with FGF10 signaling	Upregulates gene expression of pancreatic progenitor markers SOX9, PDX1, PTF1A, HNF6, PROX1 Upregulates gene expression of endocrine progenitor markers including NGN3, NKX2.2, and NKX6.1	Chen et al. (26)	√	√
	500 nM TPB		Upregulates protein expression of FOXA2, PTF1A, HNF6, and NKX6.1		√
	14 nM PMA		Downregulates protein expression of endoderm markers CDX2 and AFP		√
	50 nM TPB	Activates PKC	Upregulates gene expression of pancreatic lineage markers NGN3, NEUROD1, PTF1A, and NKX6.1 Downregulates gene expression of intestinal marker CDX2 and liver marker ALB	Rezania et al. (4)	√
	500 nM PDBu			Pagliuca et al. (7)	√
Low retinoic acid (RA) signaling	1–3 μM RA	Activates RA receptors		Various	√
	3 nM TTNPB			Schulz et al. (17)	√
	1 μM → 100 nM → 50 nM RA			Rezania et al. (7)	√
	2 μM → 100 nM → 25 nM RA			Pagliuca et al. (7)	√
γ-secretase/Notch inhibitor	DAPT	Inhibits Notch signaling	Upregulates NGN3 mRNA and protein expression in adult islets	Dror et al. (36)	√	√
			Upregulates NGN3 and NEUROD1 gene expression	Rezania et al. (18)	√
	GSiXX		Upregulates expression of β cell maturation genes Downregulates expression of pancreatic exocrine marker PTF1A	Rezania et al. (6)	√
	GSiXX + T3		Upregulates NKX6.1+insulin+GCG- β-like cells	Rezania et al. (6)	√
	1 μM XXI		Upregulates β cell gene expression	Pagliuca et al. (7)	√
T3	0.1 μM T3	Activates MAPK/ERK signaling pathway	Induces rodent pancreatic β cell proliferation	Kim et al. (42)		√
	1 μM T3		Upregulates expression of INS and mature β cell markers	Rezania et al. (6)	√
			Enhances co-expression of NKX6.1 and INS protein	Pagliuca et al. (7)
AXL	2 μM BGB324 (R428)	Inhibits AXL	Upregulates MAFA protein expression	Rezania et al. (6)	√
	GAS6	Activates AXL	Downregulates Mafa gene expression	Haase et al. (48)		√
Antioxidants	GPx-1	Antioxidants	Maintains protein expression of nuclear MAFA in diabetic rodents	Harmon et al. (22)		√
	NAC			Harmon et al. (21)		√
	Ebselen			Mahadevan et al. (20)		√
	1–2 mM NAC		Upregulates nuclear MAFA protein expression	Rezania et al. (6)	√
	0.25 mM vitamin C		Generates mature and functional human pancreatic β cells	Pagliuca et al. (7)	√
Betacellulin	BTC	Binds to ErbB-1 and ErbB-4 receptors to initiate PI3K/Akt, MAPK, STAT, and mTOR signaling pathways	Upregulates insulin secretion	Dahlhoff et al. (65)		√
			Upregulates mRNA and protein expression of IRS-2	Oh et al. (68)		√
			Induces Pax4 gene expression in rat islets	Brun et al. (70)		√
			Sustains PDX1 expression and induces β cell differentiation from hESCs	Cho et al. (71)	√
	10 ng/ml BTC		Upregulates Pdx1 gene expression and insulin production Downregulates amylase and glucagon production in mouse embryonic pancreas explants	Thowfeequ et al. (72)		√
	20 ng/ml BTC		Induces pancreatic differentiation	Pagliuca et al. (7)	√
	50 ng/ml EGF		Preserves cell mass	Schulz et al. (17)	√

BTC, Betacellulin; DAPT, N-[N-(3,5-difluorophenacetyl-l-alanyl)]-S-phenylglycine t-butyl ester; GPx-1, glutathione peroxidase-1; GSiXX, γ secretase inhibitor XX; ILV, (−)-indolactam V; NAC, N-acetylcysteine; PDBu, phorbol 12,13-dibutyrate; PMA, phorbol-12-myristate-13-acetate; T3, l-3,3′,5-Triiodothyronine; TPB, [(2S,5S)-(E,E)-8-(5-(4-(trifluoromethyl)phenyl)-2,4-pentadienoylamino) benzolactam].