Advances in β cell replacement and regeneration strategies for treating diabetes.
In the past decade, new approaches have been explored that are aimed at restoring functional β cell mass as a treatment strategy for diabetes. The two most intensely pursued strategies are β cell replacement through conversion of other cell types and β cell regeneration by enhancement of β cell replication. The approach closest to clinical implementation is the replacement of β cells with human pluripotent stem cell-derived (hPSC-derived) cells, which are currently under investigation in a clinical trial to assess their safety in humans. In addition, there has been success in reprogramming developmentally related cell types into β cells. Reprogramming approaches could find therapeutic applications by inducing β cell conversion in vivo or by reprogramming cells ex vivo followed by implantation. Finally, recent studies have revealed novel pharmacologic targets for stimulating β cell replication. Manipulating these targets or the pathways they regulate could be a strategy for promoting the expansion of residual β cells in diabetic patients. Here, we provide an overview of progress made toward β cell replacement and regeneration and discuss promises and challenges for clinical implementation of these strategies.
Jacqueline R
JR
Benthuysen
Andrea C
AC
Carrano
Maike
M
Sander
D000818:Animals; D049109:Cell Proliferation; D054338:Cell Transdifferentiation; D065150:Cellular Reprogramming; D003920:Diabetes Mellitus / Q000628:therapy*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000502:physiology / Q000637:transplantation*; D039904:Pluripotent Stem Cells / Q000637:transplantation; D012038:Regeneration
J Biol Chem. 2007 Apr 20;282(16):12030-7
17242403
J Clin Invest. 2007 Sep;117(9):2553-61
17786244
Diabetes. 1989 Jan;38(1):49-53
2642434
Diabetologia. 2016 Mar;59(3):522-32
26693711
J Biol Chem. 2003 Aug 29;278(35):32517-25
12783880
Cell Metab. 2014 Jan 7;19(1):109-21
24332968
Diabetologia. 2008 Jan;51(1):91-100
17994216
Cell Metab. 2011 Apr 6;13(4):440-9
21459328
Cell Stem Cell. 2014 Jan 2;14(1):121-30
24388175
Diabetes. 2007 Nov;56(11):2732-43
17686945
Nature. 2008 Oct 2;455(7213):627-32
18754011
Proc Natl Acad Sci U S A. 2013 Oct 1;110(40):16109-14
24043787
Diabetes Care. 2013 Jan;36(1):111-7
22875233
Stem Cell Res. 2014 May;12(3):807-14
24788136
Br J Obstet Gynaecol. 1978 Nov;85(11):818-20
363135
Cell. 2012 Sep 14;150(6):1223-34
22980982
Dev Cell. 2015 Mar 9;32(5):535-45
25662175
J Clin Invest. 2007 Jan;117(1):246-57
17200721
Nature. 2006 Sep 21;443(7109):345-9
16988714
Elife. 2015 Jul 28;4:null
26218223
J Endocrinol. 2006 Mar;188(3):481-92
16522728
N Engl J Med. 2006 Sep 28;355(13):1318-30
17005949
Am J Transl Res. 2013;5(2):184-99
23573363
Diabetes Obes Metab. 2008 Nov;10 Suppl 4:32-42
18834431
Proc Natl Acad Sci U S A. 2009 Feb 3;106(5):1427-32
19164755
Stem Cells. 2010 Sep;28(9):1630-8
20653050
PLoS One. 2012;7(4):e35801
22563404
Cell Metab. 2015 Oct 6;22(4):619-32
26321660
Nature. 2006 Sep 28;443(7110):453-7
16957737
PLoS One. 2014 Nov 14;9(11):e113022
25397325
J Endocrinol. 2004 Dec;183(3):469-76
15590973
Diabetes. 2016 May;65(5):1283-96
26868297
Ann N Y Acad Sci. 1991;621:327-36
1713432
Cell. 2013 May 9;153(4):747-58
23623304
J Biol Chem. 2010 Aug 6;285(32):24477-86
20529852
Dev Cell. 2009 Mar;16(3):358-73
19289082
Diabetologia. 1983 Nov;25(5):439-43
6360782
Diabetes. 2014 Mar;63(3):819-31
24556859
Transplantation. 2011 Apr 15;91(7):714-22
21297554
Cell Stem Cell. 2013 Feb 7;12(2):224-37
23318056
J Clin Endocrinol Metab. 2010 Oct;95(10):E234-9
20660050
J Biol Chem. 2016 Feb 26;291(9):4614-25
26740620
Cell. 2007 Aug 10;130(3):456-69
17693256
Endocrinology. 2015 Sep;156(9):3137-46
26151356
Endocrinology. 2008 May;149(5):2251-60
18202127
Cell. 2009 Aug 7;138(3):449-62
19665969
Proc Natl Acad Sci U S A. 2014 Dec 9;111(49):17612-7
25404292
Gastroenterology. 2010 May;138(5):1954-65
20138042
Proc Natl Acad Sci U S A. 2013 Nov 19;110(47):19054-8
24167261
Diabetologia. 2010 Dec;53(12):2579-88
20886204
Diabetes. 2008 Apr;57(4):945-57
18174523
Nat Biotechnol. 2014 Nov;32(11):1121-33
25211370
Nature. 2010 Apr 22;464(7292):1149-54
20364121
PLoS One. 2014 Apr 02;9(4):e93651
24695557
Mol Cell Endocrinol. 2004 May 31;220(1-2):41-50
15196698
Diabetes. 2007 Jul;56(7):1792-801
17400928
Diabetes. 2002 Oct;51(10):2877-85
12351422
J Clin Invest. 1987 Feb;79(2):616-9
3543057
Diabetes. 2016 Jul;65(7):2081-93
26993067
J Clin Invest. 2013 Nov;123(11):4849-58
24216481
Diabetes. 2002 Apr;51(4):966-76
11916914
Pancreas. 1992;7(3):367-75
1594559
Diabetes. 2015 Jun;64(6):1872-85
25999530
Diabetologia. 2011 Mar;54(3):572-82
20936253
Endocrinology. 2000 Dec;141(12):4600-5
11108273
Nat Med. 2016 Mar;22(3):306-11
26808346
Nat Biotechnol. 2006 Nov;24(11):1392-401
17053790
Diabetes. 2016 Jun;65(6):1660-71
26953159
Diabetes. 2003 Jul;52(7):1738-48
12829641
Genes Dev. 2009 Apr 15;23 (8):906-11
19390085
Diabetes. 2011 Nov;60(11):2872-82
21926270
Nat Commun. 2016 May 10;7:11463
27163171
Cell. 2014 Oct 9;159(2):428-39
25303535
Cell Rep. 2016 Apr 19;15(3):460-70
27068459
Endocrinology. 1993 Feb;132(2):879-87
8425500
PLoS One. 2012;7(1):e28808
22242153
Nat Med. 2000 May;6(5):568-72
10802714
Ann N Y Acad Sci. 2013 Apr;1281:92-105
23363033
Nat Med. 2003 May;9(5):596-603
12704384
Nat Rev Endocrinol. 2015 Apr;11(4):201-12
25687999
J Clin Invest. 2008 Nov;118(11):3629-38
18846252
Diabetes. 2008 Jun;57(6):1584-94
18334605
Nat Biotechnol. 2014 Jan;32(1):76-83
24240391
Am J Physiol. 1971 Jul;221(1):202-8
4933588
Diabetes. 2014 Mar;63(3):994-1007
24215793
J Clin Oncol. 2010 Jan 10;28(2):245-55
19917848
Biochem J. 1999 Dec 15;344 Pt 3:649-58
10585851
Proc Natl Acad Sci U S A. 2008 Apr 1;105(13):5266-70
18362359
Tumour Biol. 2015 Jan;36(1):399-408
25266798
Nat Med. 2012 Dec;18(12):1847-56
23142820
Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7475-80
11404474
Diabetologia. 2004 Feb;47(2):259-65
14666367
Curr Protoc Chem Biol. 2014 Sep 09;6(3):157-68
25205564
Oncotarget. 2014 Nov 30;5(22):11252-68
25361004
Cell Metab. 2012 Jun 6;15(6):885-94
22608007
J Biol Chem. 2009 Mar 20;284(12):7832-42
19144649
Proc Natl Acad Sci U S A. 2010 Aug 24;107(34):15099-104
20696901
Am J Physiol Endocrinol Metab. 2003 Jan;284(1):E7-12
12485807
Diabetologia. 2010 Dec;53(12 ):2600-10
20821187
Nature. 2004 May 6;429(6987):41-6
15129273
Cell Stem Cell. 2016 Mar 3;18(3):410-21
26908146
Am J Physiol Endocrinol Metab. 2011 Jan;300(1):E221-30
20978233
Nature. 2011 Oct 12;478(7369):349-55
21993628
Endocrinology. 1999 Feb;140(2):778-83
9927305
Diabetes. 2010 Nov;59(11):2846-53
20699420
Cell Metab. 2015 Jul 7;22(1):77-85
26094891
Transpl Int. 2011 Aug;24(8):856-64
21627696
Diabetes. 2015 Nov;64(11):3784-97
26159175
Diabetes. 2012 Sep;61(9):2205-13
22751699
PLoS One. 2014 Aug 12;9(8):e104112
25117518
Nat Biotechnol. 2016 Mar;34(3):345-52
26807527
Cell. 1997 Feb 21;88(4):561-72
9038347
Nat Commun. 2014 Jun 30;5:4242
24979718
Diabetologia. 2010 Oct;53(10):2167-76
20523966
J Cell Biochem. 2004 Oct 1;93(2):242-50
15368352
J Endocrinol. 2010 Dec;207(3):265-79
20847227
Diabetes. 2004 Dec;53 Suppl 3:S225-32
15561916
Nat Biotechnol. 2008 Apr;26(4):443-52
18288110
Dev Cell. 2009 Jul;17 (1):142-9
19619499
Gene Ther. 2010 Nov;17(11):1411-20
20508600
Diabetes. 2010 Oct;59(10):2390-9
20622167
Diabetes. 2014 Mar;63(3):1021-31
24009262
PLoS Genet. 2013 Oct;9(10):e1003934
24204325
Mol Endocrinol. 2010 Aug;24(8):1605-14
20592160
Diabetes. 2011 Oct;60(10 ):2546-59
21911744
Cell. 2014 Oct 23;159(3):691-6
25417115
Diabetes. 2012 Aug;61(8):2004-15
22586588
J Clin Invest. 2015 Oct 1;125(10):3831-46
26389675
Diabetes. 2014 Apr;63(4):1283-8
24353178
Cell Rep. 2015 Oct 6;13(1):15-22
26387957
Diabetes. 2012 Aug;61(8):2016-29
22740171
Nat Commun. 2015 Oct 26;6:8372
26496802
Diabetes Care. 2009 Oct;32(10):1887-9
19549731
Diabetes. 2013 Jul;62(7):2157-63
23801714
Proc Natl Acad Sci U S A. 2007 May 22;104(21):8977-82
17416680
Cell Metab. 2016 Jan 12;23 (1):194-205
26701651
Diabetes. 2001 Oct;50(10):2237-43
11574404
J Biomol Screen. 2012 Apr;17(4):509-18
22156222
Diabetes. 1999 Dec;48(12):2270-6
10580413
J Clin Endocrinol Metab. 1999 Mar;84(3):863-8
10084562
Semin Cell Dev Biol. 2013 Jan;24(1):11-21
23022232
Nature. 2014 Oct 23;514(7523):503-7
25141178
J Surg Res. 2004 Sep;121(1):141-50
15313388
Mol Endocrinol. 2009 Oct;23(10):1702-12
19574445
J Biol Chem. 2000 May 19;275(20):15399-406
10809775
Diabetes. 2013 Aug;62(8):2843-8
23630298
Metabolism. 1976 Dec;25(12):1567-74
994838
J Am Chem Soc. 2013 Feb 6;135(5):1669-72
23330637
Diabetes Care. 1983 Jan-Feb;6(1):95-9
6341018
Transplantation. 2007 Dec 27;84(12):1576-83
18165767
Diabetologia. 2008 Apr;51(4):623-31
18219478
Nat Med. 2010 Jul;16(7):804-8
20581837
Science. 1997 Mar 28;275(5308):1930-4
9072970
Nat Genet. 2012 Mar 11;44(4):406-12, S1
22406641
Tumour Biol. 2015 Sep;36(9):7195-204
25894372
Diabetes. 2013 May;62(5):1569-80
23305647
Dev Cell. 2012 Jul 17;23(1):21-34
22814600
Diabetes. 2003 Apr;52(4):974-83
12663469
Diabetologia. 2013 Sep;56(9):1987-98
23771205
Horm Metab Res. 1997 Jun;29(6):301-7
9230352
Diabetes. 2005 Sep;54(9):2557-67
16123343
Diabetes. 1995 Dec;44(12):1447-57
7589853
Mol Ther. 2016 Feb;24(2):251-60
26435408
Proc Natl Acad Sci U S A. 2012 Mar 6;109(10):3915-20
22345561
Endocrinology. 1992 Mar;130(3):1459-66
1537300
Proc Natl Acad Sci U S A. 1997 May 27;94(11):5599-604
9159118
Dev Cell. 2013 Jul 15;26(1):86-100
23810513
J Biol Chem. 2003 Aug 22;278(34):31950-7
12775714
Genes Dev. 2009 Apr 15;23 (8):975-85
19390090
Nat Med. 2016 Apr;22(4):412-20
26950362
Diabetes. 2009 Mar;58(3):663-72
19073772
J Clin Invest. 2013 Mar;123(3):1275-84
23434589
Cell Rep. 2014 Mar 27;6(6):1046-58
24613355
J Clin Endocrinol Metab. 2012 Sep;97(9):3197-206
22745242
Diabetes. 1973 Sep;22(9):687-93
4125576
Mol Endocrinol. 2016 Jan;30(1):133-43
26649805