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. 2022 Jan 27;9:734597. doi: 10.3389/fcell.2021.734597

TABLE 1.

Human beta cell mitogens and their potencies.

Mitogen References Experimental model Labelling index (control vs mitogen), %
 Cell cycle regulators
 Signaling pathway
Ki67 BrdU EdU pHH3 Activators Inhibitors
PDGF Chen et al., 2011 In vitro (p) 0.5 vs. 3(effect only in juvenile) PDGFR -> Erk activation -> Ezh2 induction
WS6 Shen et al., 2013 In vitro (p) 0.1 vs. 3 Inhibition of IKK -> NFkB translocation to the nucleus
In vitro (d) 0.5 vs. 3
Boerner et al., 2015 In vitro (p) 0.3 vs. 0.8
Wang et al., 2015c In vitro (d) NS
WS3 Dirice et al., 2016 In vitro (d) NS
Harmine Wang et al., 2015c In vitro (d) 0.1 vs. 1.2 0.1 vs. 1 CDK1, Cyclin A1, Cyclin E2, CDC25A, CDC25C, FOXM1, E2F1, E2F2, E2F7, E2F8 p15, p16, p57 Inhibition of DYRK1A -> NFAT translocation to the nucleus
Aamodt et al., 2016 In vitro (d) 0 vs. 0.4
Dirice et al., 2016 In vitro (d) 0.5 vs. 2.5
Kumar et al., 2018 In vitro (d) 0.1 vs. 2.5
Wang P. et al., 2019 In vitro (d) 0 vs. 2.5 0 vs. 2.5 0 vs. 0.4 CDK1, Cyclin A1, Cyclin E2, CDC25A, FOXM1 p57
In vivo 0.5 vs. 1.2
Ackeifi et al., 2020a In vitro (d) 0.1 vs. 3
Ackeifi et al., 2020b In vitro (d) 0 vs. 2.5 0.2 vs. 2 CDK1, Cyclin A1, Cyclin A2, Cyclin E2, CDC25A, c-Myc, FOXM1 p15, p16, p57
In vivo 0.4 vs. 0.8
Rosado-Olivieri et al., 2020 In vitro (sc) 1 vs. 2.5
INDY Wang et al., 2015c In vitro (d) 0 vs. 1.6 CDK1, Cyclin A1, Cyclin E2, CDC25A, CDC25C, FOXM1, E2F1, E2F2, E2F7, E2F8 p15, p16, p57
Wang P. et al., 2019 In vitro (d) 0.1 vs. 2.5
Ackeifi et al., 2020a In vitro (d) 0.1 vs. 3
5-IT Dirice et al., 2016 In vitro (d) 0.1 vs. 5 CENPA, MCM2, MCM4, MCM5, CDC6, Cyclin B1, CDC20, TOP2A, RFC4
In vivo 0.1 vs. 0.4 0.1 vs. 0.4 0 vs. 0.2
Ackeifi et al., 2020a In vitro (d) 0.1 vs. 2.8
CC-401 Abdolazimi et al., 2018 In vitro (d) 0.2 vs. 0.7
Ackeifi et al., 2020a In vitro (d) 0.1 vs. 0.8
Leucettine-41 Wang P. et al., 2019 In vitro (d) 0.1 vs. 2
Ackeifi et al., 2020a In vitro (d) 0.1 vs. 4.3
TG003 Ackeifi et al., 2020a In vitro (d) 0.1 vs. 2.3
AZ191 Ackeifi et al., 2020a In vitro (d) 0.1 vs. 0.5
OTS167-derivatives Allegretti et al., 2020 In vitro (d) 8-fold
JAK3 inhibitor VI Abdolazimi et al., 2018 In vitro (d) 0.2 vs. 0.6
GNF7156 Shen et al., 2015 In vitro (d) 0 vs. 3 Inhibition of DYRK1A and GSK-3 beta -> NFAT translocation to the nucleus
GNF4877 In vitro (d) In vitro (p) 0 vs. 6 0.2 vs. 3
In vivo 1 vs. 3.5
Ackeifi et al., 2020a In vitro (d) 0.1 vs. 4
Tideglusib Chiron99021 Ackeifi et al., 2020a Ackeifi et al., 2020a Tsonkova et al., 2018 In vitro (d) In vitro (d) In vitro (e) NS NS 0 vs. 20 Inhibition of GSK-3 beta -> NFAT translocation to the nucleus
PSN632408 Ansarullah et al., 2016 In vivo 0.7 vs. 2.5 1.5 vs. 6.3 GLP1R -> Ca2+ increase-> calcineurin increase-> NFAT translocation to the nucleus
GLP-1(7-36)amide Ackeifi et al., 2020b In vitro (d) NS NS CDK4, Cyclin B3 p16, p18, p21
Exendin-4 Aamodt et al., 2016 In vitro (d) NS
Muhammad et al., 2017 In vitro (p) 2-fold
Dai et al., 2017 In vivo juvenile:1.9 vs. 4adult:0.4 vs. 0.5 NFATC1, NFATC3, NFATC4, Cyclin A1, CDK1, FOXM1, EGR2, EGR3
Ackeifi et al., 2020b In vivo 0.4 vs. 0.6
OPG Kondegowda et al., 2015 In vitro (d) 0.4 vs. 1.3 Inhibition of RANKL/RANK pathway ->GSK-3 beta inhibition, CREB-stimulation
DMB In vitro (d) 0.4 vs. 0.8
In vivo 0 vs. 0.1
SerpinB1 Silvestat El Ouaamari et al., 2016 In vitro (p) In vitro (p) In vivo 0.01 vs. 0.05 0.1 vs. 0.05 0 vs. 0.1 Inhibition of GSK-3 beta, alteration of MAPK, PRKAR2B-> NFAT translocation to the nucleus
Glucose Stamateris et al., 2016 In vitro (d) Up to 1.2 Activation of mTOR pathway
SB431542 Dhawan et al., 2016 In vivo 0.2 vs. 0.5 0 vs. 0.3 0.05 vs. 0.1 p16 Inhibition of TGF-beta pathway
ALKV Inh. II Abdolazimi et al., 2018 In vitro (d) NS
D4476 In vitro (d) NS
SB431542 Hakonen et al., 2018 In vitro (p) NS
LY364947 Wang P. et al., 2019 In vitro (d) NS NS NS p15, p16, p21, p57
GW788388 In vivo 0.5 vs. 1
GABA Purwana et al., 2014 In vivo 0.5 vs. 2.3 GABAA/BR -> Ca2+ increase -> Activation of PI3K/Akt pathway, CREB activation
Aamodt et al., 2016 In vitro (d) NS
Prud’homme et al., 2017 In vitro (p) 0.5 vs. 3.2
Tian et al., 2017a In vitro (p) up to 1.2
Lesogaberan Tian et al., 2017b In vitro (p) 2.7-fold
In vivo 0.5 vs. 0.9 0.9 vs. 2.3
LIF Rosado-Olivieri et al., 2020 In vitro (sc) 1 vs. 1.5 Cyclin A2, Cyclin B1, Cyclin B2, Cyclin E2, CDK2, CDK4 p16, p18, p19 Activation of LIF pathway:LIFR-STAT3-CEBPD activation
In vitro (d) Cyclin B1, Cyclin B2, Cyclin D1, Cyclin E2, CDK2
In vivo 0.4 vs. 1.5
MANF Hakonen et al., 2018 In vitro (p) NS Inhibition of NF-κB pathway
MI-2 Chamberlain et al., 2014 In vitro (p) 0 vs. 0.6 Inhibition of menin -> activation of MAPK
MI-2-2 Muhammad et al., 2017 In vitro (p) 2.3-fold

NS, not significant.

For each mitogen, the available information is:

– Mitogen applied (column 1);

– Reference (column 2);

– Model used (column 3): pstands for primary islets; d stands for dispersed beta cells; sc stands for human stem cell-derived beta cells; e stands for EndoC-βH1 cell line; and in vivo implies human beta cells/islets engrafted into mouse;

– Proliferation index (columns 4–7). The values are presented as index from control beta cells vs. the cells treated with mitogens; by default, the values are given in percentage and for the cases with different units, the units are indicated (for example, fold change). Depending on the proliferation markers assessed (Ki67, BrdU, EdU, or pHH3), the values are situated in the column dedicated for the corresponding marker;

– Effect on cell cycle regulators: upregulated activators (column 8) and downregulated inhibitors (column 9) in response to mitogen treatment;

– Signaling pathway through which the mitogen acts (column 10).