Islet-Like Structures Generated In Vitro from Adult Human Liver Stem Cells Revert Hyperglycemia in Diabetic SCID Mice.
Adult
Animals
Biomarkers
/ metabolism
C-Peptide
/ metabolism
Cell Differentiation
/ drug effects
Diabetes Mellitus, Experimental
/ complications
Gene Expression Regulation
/ drug effects
Glucose
/ pharmacology
Humans
Hyperglycemia
/ complications
Insulin-Secreting Cells
/ drug effects
Islets of Langerhans
/ physiology
Liver
/ cytology
Male
Mice, SCID
Phenotype
Protamines
/ pharmacology
Spheroids, Cellular
/ cytology
Stem Cells
/ cytology
3D culture
Diabetes
Insulin-producing stem cells
Liver stem cells
Pancreatic islets
Pancreatic β cells
Journal
Stem cell reviews and reports
ISSN: 2629-3277
Titre abrégé: Stem Cell Rev Rep
Pays: United States
ID NLM: 101752767
Informations de publication
Date de publication:
02 2019
02 2019
Historique:
pubmed:
8
9
2018
medline:
25
7
2020
entrez:
8
9
2018
Statut:
ppublish
Résumé
A potential therapeutic strategy for diabetes is the transplantation of induced-insulin secreting cells. Based on the common embryonic origin of liver and pancreas, we studied the potential of adult human liver stem-like cells (HLSC) to generate in vitro insulin-producing 3D spheroid structures (HLSC-ILS). HLSC-ILS were generated by a one-step protocol based on charge dependent aggregation of HLSC induced by protamine. 3D aggregation promoted the spontaneous differentiation into cells expressing insulin and several key markers of pancreatic β cells. HLSC-ILS showed endocrine granules similar to those seen in human β cells. In static and dynamic in vitro conditions, such structures produced C-peptide after stimulation with high glucose. HLSC-ILS significantly reduced hyperglycemia and restored a normo-glycemic profile when implanted in streptozotocin-diabetic SCID mice. Diabetic mice expressed human C-peptide and very low or undetectable levels of murine C-peptide. Hyperglycemia and a diabetic profile were restored after HLSC-ISL explant. The gene expression profile of in vitro generated HLSC-ILS showed a differentiation from HLSC profile and an endocrine commitment with the enhanced expression of several markers of β cell differentiation. The comparative analysis of gene expression profiles after 2 and 4 weeks of in vivo implantation showed a further β-cell differentiation, with a genetic profile still immature but closer to that of human islets. In conclusion, protamine-induced spheroid aggregation of HLSC triggers a spontaneous differentiation to an endocrine phenotype. Although the in vitro differentiated HLSC-ILS were immature, they responded to high glucose with insulin secretion and in vivo reversed hyperglycemia in diabetic SCID mice.
Identifiants
pubmed: 30191384
doi: 10.1007/s12015-018-9845-6
pii: 10.1007/s12015-018-9845-6
pmc: PMC6510809
doi:
Substances chimiques
Biomarkers
0
C-Peptide
0
Protamines
0
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
93-111Références
Development. 2000 Dec;127(24):5533-40
pubmed: 11076772
Diabetes. 2001 Feb;50(2):270-6
pubmed: 11272136
Science. 2001 May 18;292(5520):1389-94
pubmed: 11326082
Endocrine. 2001 Apr;14(3):295-302
pubmed: 11444425
Diabetes. 2001 Aug;50(8):1691-7
pubmed: 11473026
Development. 2002 May;129(10):2367-79
pubmed: 11973269
J Biol Chem. 2003 Aug 22;278(34):31950-7
pubmed: 12775714
Stem Cells. 2004;22(3):265-74
pubmed: 15153604
J Am Soc Nephrol. 2005 Jan;16(1):27-45
pubmed: 15563560
Proc Natl Acad Sci U S A. 2005 May 31;102(22):7964-9
pubmed: 15899968
Nat Biotechnol. 2005 Jun;23(6):699-708
pubmed: 15940242
Mol Ther. 2005 Jul;12(1):28-32
pubmed: 15963917
Nat Biotechnol. 2005 Jul;23(7):857-61
pubmed: 16003374
Diabetes. 2005 Sep;54(9):2568-75
pubmed: 16123344
Nat Biotechnol. 2005 Dec;23(12):1534-41
pubmed: 16258519
Ann Med. 2005;37(7):521-32
pubmed: 16278165
Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2334-9
pubmed: 16461897
APMIS. 2005 Nov-Dec;113(11-12):858-75
pubmed: 16480455
Dev Growth Differ. 2006 Jun;48(5):323-32
pubmed: 16759282
Cloning Stem Cells. 2006 Summer;8(2):96-107
pubmed: 16776601
Stem Cells. 2006 Dec;24(12):2840-50
pubmed: 16945998
Nat Biotechnol. 2006 Nov;24(11):1392-401
pubmed: 17053790
Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):3853-8
pubmed: 17360442
Diabetologia. 2007 Jun;50(6):1228-38
pubmed: 17457565
Blood. 2007 Oct 1;110(7):2440-8
pubmed: 17536014
Cell Death Differ. 2007 Nov;14(11):1860-71
pubmed: 17612586
Hepatology. 2007 Sep;46(3):898-905
pubmed: 17705277
Biochemistry. 2007 Dec 18;46(50):14461-7
pubmed: 18027971
Biochem J. 2008 Apr 1;411(1):41-51
pubmed: 18039179
Nat Biotechnol. 2008 Apr;26(4):443-52
pubmed: 18288110
Am J Transplant. 2008 Oct;8(10):1990-7
pubmed: 18828765
Vitam Horm. 2009;80:473-506
pubmed: 19251047
Nat Chem Biol. 2009 Apr;5(4):258-65
pubmed: 19287398
Lancet. 2009 May 23;373(9677):1808-17
pubmed: 19465236
Life Sci. 2009 Oct 7;85(15-16):549-56
pubmed: 19747492
J Biol Chem. 2009 Nov 27;284(48):33509-20
pubmed: 19755420
Mol Cell Biol. 2009 Dec;29(24):6366-79
pubmed: 19805515
Dev Cell. 2010 Feb 16;18(2):175-89
pubmed: 20159590
J Histochem Cytochem. 2010 Jun;58(6):567-76
pubmed: 20197491
Proc Natl Acad Sci U S A. 2010 Aug 3;107(31):13724-9
pubmed: 20643923
Acta Diabetol Lat. 1990 Jul-Sep;27(3):185-95
pubmed: 2075782
Diabetes. 2011 Jan;60(1):239-47
pubmed: 20971966
Cytotherapy. 2011 Mar;13(3):279-93
pubmed: 21039304
Cell Metab. 2010 Dec 1;12(6):619-32
pubmed: 21109194
Development. 2011 Feb;138(3):431-41
pubmed: 21205788
Development. 2011 Mar;138(5):861-71
pubmed: 21270052
J Biol Chem. 2011 Mar 25;286(12):10449-56
pubmed: 21278380
Cell Transplant. 2011;20(9):1343-9
pubmed: 21396168
Eur J Endocrinol. 2011 Jun;164(6):919-26
pubmed: 21422196
Nat Med. 2011 Jun 19;17(7):888-92
pubmed: 21685896
Trends Endocrinol Metab. 2011 Sep;22(9):364-73
pubmed: 21719305
Nat Biotechnol. 2011 Jul 31;29(8):750-6
pubmed: 21804561
BMC Genomics. 2012 Jan 19;13:33
pubmed: 22260730
PLoS One. 2012;7(5):e37004
pubmed: 22623968
Diabetes. 2012 Aug;61(8):2016-29
pubmed: 22740171
Expert Opin Biol Ther. 2012 Oct;12(10):1347-60
pubmed: 22784238
Mol Cells. 2012 Aug;34(2):193-200
pubmed: 22820919
Hepatology. 2013 Jan;57(1):311-9
pubmed: 22829291
Mol Cell Endocrinol. 2012 Nov 25;364(1-2):36-45
pubmed: 22939844
Annu Rev Physiol. 2013;75:155-79
pubmed: 22974438
Diabetologia. 2012 Dec;55(12):3284-95
pubmed: 23011350
Physiol Rev. 2013 Jan;93(1):137-88
pubmed: 23303908
PLoS Genet. 2013;9(1):e1003274
pubmed: 23382704
J Clin Invest. 2013 Mar;123(3):1275-84
pubmed: 23434589
J Cell Sci. 2013 Aug 15;126(Pt 16):3638-48
pubmed: 23750005
Diabetologia. 2013 Sep;56(9):1987-98
pubmed: 23771205
Stem Cells. 2013 Nov;31(11):2432-42
pubmed: 23897760
Stem Cell Res. 2014 Jan;12(1):194-208
pubmed: 24257076
Cell Metab. 2014 Feb 4;19(2):259-71
pubmed: 24506867
Protein Cell. 2014 Mar;5(3):203-13
pubmed: 24633815
Endocrinology. 2014 Oct;155(10):3757-68
pubmed: 24932805
Nat Biotechnol. 2014 Nov;32(11):1121-33
pubmed: 25211370
Biochem Biophys Res Commun. 2014 Oct 24;453(3):405-10
pubmed: 25268319
Cell. 2014 Oct 9;159(2):428-39
pubmed: 25303535
EMBO J. 2015 Jul 2;34(13):1759-72
pubmed: 25908839
J Histochem Cytochem. 2015 Aug;63(8):575-91
pubmed: 26216135
Islets. 2016;8(1):13-34
pubmed: 26404721
J Diabetes. 2017 Feb;9(2):168-179
pubmed: 27038181
Nat Commun. 2016 Apr 11;7:11247
pubmed: 27063289
Nat Commun. 2016 May 10;7:11463
pubmed: 27163171
PLoS One. 2016 May 31;11(5):e0156204
pubmed: 27243814
Am J Transl Res. 2017 Mar 15;9(3):874-886
pubmed: 28386318
Physiol Rev. 2018 Jul 1;98(3):1143-1167
pubmed: 29717931
Endocrinology. 1994 Oct;135(4):1651-60
pubmed: 7925129
Mol Cell Endocrinol. 1998 Apr 30;139(1-2):7-13
pubmed: 9705069