Bone marrow stromal cells from β-thalassemia patients have impaired hematopoietic supportive capacity.
Bone marrow
Cell stress
Stem cell transplantation
Stem cells
Transplantation
Journal
The Journal of clinical investigation
ISSN: 1558-8238
Titre abrégé: J Clin Invest
Pays: United States
ID NLM: 7802877
Informations de publication
Date de publication:
25 02 2019
25 02 2019
Historique:
received:
26
06
2018
accepted:
17
01
2019
entrez:
5
3
2019
pubmed:
5
3
2019
medline:
26
2
2020
Statut:
epublish
Résumé
The human bone marrow (BM) niche contains a population of mesenchymal stromal cells (MSCs) that provide physical support and regulate hematopoietic stem cell (HSC) homeostasis. β-Thalassemia (BT) is a hereditary disorder characterized by altered hemoglobin beta-chain synthesis amenable to allogeneic HSC transplantation and HSC gene therapy. Iron overload (IO) is a common complication in BT patients affecting several organs. However, data on the BM stromal compartment are scarce. MSCs were isolated and characterized from BM aspirates of healthy donors (HDs) and BT patients. The state of IO was assessed and correlated with the presence of primitive MSCs in vitro and in vivo. Hematopoietic supportive capacity of MSCs was evaluated by transwell migration assay and 2D coculture of MSCs with human CD34+ HSCs. In vivo, the ability of MSCs to facilitate HSC engraftment was tested in a xenogenic transplant model, whereas the capacity to sustain human hematopoiesis was evaluated in humanized ossicle models. We report that, despite iron chelation, BT BM contains high levels of iron and ferritin, indicative of iron accumulation in the BM niche. We found a pauperization of the most primitive MSC pool caused by increased ROS production in vitro which impaired MSC stemness properties. We confirmed a reduced frequency of primitive MSCs in vivo in BT patients. We also discovered a weakened antioxidative response and diminished expression of BM niche-associated genes in BT-MSCs. This caused a functional impairment in MSC hematopoietic supportive capacity in vitro and in cotransplantation models. In addition, BT-MSCs failed to form a proper BM niche in humanized ossicle models. Our results suggest an impairment in the mesenchymal compartment of BT BM niche and highlight the need for novel strategies to target the niche to reduce IO and oxidative stress before transplantation. This work was supported by the SR-TIGET Core grant from Fondazione Telethon and by Ricerca Corrente.
Sections du résumé
BACKGROUND
The human bone marrow (BM) niche contains a population of mesenchymal stromal cells (MSCs) that provide physical support and regulate hematopoietic stem cell (HSC) homeostasis. β-Thalassemia (BT) is a hereditary disorder characterized by altered hemoglobin beta-chain synthesis amenable to allogeneic HSC transplantation and HSC gene therapy. Iron overload (IO) is a common complication in BT patients affecting several organs. However, data on the BM stromal compartment are scarce.
METHODS
MSCs were isolated and characterized from BM aspirates of healthy donors (HDs) and BT patients. The state of IO was assessed and correlated with the presence of primitive MSCs in vitro and in vivo. Hematopoietic supportive capacity of MSCs was evaluated by transwell migration assay and 2D coculture of MSCs with human CD34+ HSCs. In vivo, the ability of MSCs to facilitate HSC engraftment was tested in a xenogenic transplant model, whereas the capacity to sustain human hematopoiesis was evaluated in humanized ossicle models.
RESULTS
We report that, despite iron chelation, BT BM contains high levels of iron and ferritin, indicative of iron accumulation in the BM niche. We found a pauperization of the most primitive MSC pool caused by increased ROS production in vitro which impaired MSC stemness properties. We confirmed a reduced frequency of primitive MSCs in vivo in BT patients. We also discovered a weakened antioxidative response and diminished expression of BM niche-associated genes in BT-MSCs. This caused a functional impairment in MSC hematopoietic supportive capacity in vitro and in cotransplantation models. In addition, BT-MSCs failed to form a proper BM niche in humanized ossicle models.
CONCLUSION
Our results suggest an impairment in the mesenchymal compartment of BT BM niche and highlight the need for novel strategies to target the niche to reduce IO and oxidative stress before transplantation.
FUNDING
This work was supported by the SR-TIGET Core grant from Fondazione Telethon and by Ricerca Corrente.
Identifiants
pubmed: 30830876
pii: 123191
doi: 10.1172/JCI123191
pmc: PMC6436882
doi:
pii:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1566-1580Références
Blood. 2007 Nov 15;110(10):3499-506
pubmed: 17664353
Nature. 2014 Jan 16;505(7483):327-34
pubmed: 24429631
Cell Tissue Kinet. 1970 Oct;3(4):393-403
pubmed: 5523063
Hematology Am Soc Hematol Educ Program. 2017 Dec 8;2017(1):272-277
pubmed: 29222266
Ann N Y Acad Sci. 2012 Aug;1266:72-7
pubmed: 22901259
Lancet Infect Dis. 2006 Apr;6(4):226-33
pubmed: 16554247
Cell Metab. 2010 Oct 6;12(4):321-327
pubmed: 20889125
Ann N Y Acad Sci. 2010 Aug;1202:134-40
pubmed: 20712784
Nat Rev Genet. 2001 Apr;2(4):245-55
pubmed: 11283697
Curr Opin Hematol. 2000 Nov;7(6):358-63
pubmed: 11055509
Bone. 2019 Feb;119:8-12
pubmed: 29778716
Blood. 2012 Jul 12;120(2):473-6
pubmed: 22645178
Bone Marrow Transplant. 2018 Feb;53(2):169-174
pubmed: 29035392
Immunity. 2016 Mar 15;44(3):492-504
pubmed: 26982356
Aging (Albany NY). 2011 Oct;3(10):920-33
pubmed: 21990129
Lancet. 2012 Jan 28;379(9813):373-83
pubmed: 21908035
Life Sci. 2011 Aug 15;89(7-8):250-8
pubmed: 21722651
Can J Cardiol. 2009 Apr;25(4):213-8
pubmed: 19340344
Antioxid Redox Signal. 2014 Apr 20;20(12):1881-90
pubmed: 23066813
Hematol Oncol Clin North Am. 2017 Oct;31(5):835-852
pubmed: 28895851
Stem Cells Dev. 2017 Jan 15;26(2):71-76
pubmed: 27750026
Stem Cells Dev. 2015 May 15;24(10):1150-63
pubmed: 25603196
Bone Marrow Transplant. 2011 Feb;46(2):200-7
pubmed: 20400983
Exp Hematol. 2002 Jul;30(7):783-91
pubmed: 12135677
Haematologica. 2014 May;99(5):811-20
pubmed: 24790059
Int J Hematol. 2017 Jul;106(1):45-54
pubmed: 28534115
J Clin Oncol. 2000 Jan;18(2):307-16
pubmed: 10637244
Hematology Am Soc Hematol Educ Program. 2010;2010:445-50
pubmed: 21239833
Lancet. 2018 Jan 13;391(10116):155-167
pubmed: 28774421
Int J Mol Sci. 2017 Dec 20;18(12):
pubmed: 29261151
Haematologica. 2009 Feb;94(2):173-84
pubmed: 19066333
Biol Blood Marrow Transplant. 2005 May;11(5):389-98
pubmed: 15846293
Biochim Biophys Acta. 2012 Mar;1820(3):403-10
pubmed: 21855608
Antioxid Redox Signal. 2008 Jun;10(6):997-1030
pubmed: 18327971
Nature. 2010 Aug 12;466(7308):829-34
pubmed: 20703299
Nat Rev Genet. 2006 Sep;7(9):715-27
pubmed: 16983801
Bone Marrow Transplant. 2016 Apr;51(4):536-41
pubmed: 26752139
Sci Rep. 2016 Nov 25;6:37827
pubmed: 27886253
N Engl J Med. 2012 Dec 13;367(24):2305-15
pubmed: 23234514
Development. 2014 Nov;141(22):4206-18
pubmed: 25371358
Antioxid Redox Signal. 2014 Oct 10;21(11):1605-19
pubmed: 24762207
Transplantation. 2016 Apr;100(4):925-32
pubmed: 26457600
Free Radic Biol Med. 2013 Jan;54:26-39
pubmed: 23085514
Hematology Am Soc Hematol Educ Program. 2017 Dec 8;2017(1):265-271
pubmed: 29222265
Eur J Haematol. 2014 Aug;93(2):118-28
pubmed: 24628561
Cell Stem Cell. 2013 Oct 3;13(4):392-402
pubmed: 24094322
Front Cell Dev Biol. 2017 Aug 23;5:69
pubmed: 28884113
Int J Oncol. 2013 May;42(5):1822-32
pubmed: 23483119
J Clin Invest. 2017 Feb 1;127(2):543-548
pubmed: 28067666
J Orthop Res. 1991 Sep;9(5):641-50
pubmed: 1870029
FEBS Lett. 2000 Mar 10;469(2-3):208-12
pubmed: 10713272
Lancet. 2008 May 10;371(9624):1579-86
pubmed: 18468541
J Hepatol. 2016 Oct;65(4):758-768
pubmed: 27262757
Cytotherapy. 2016 Dec;18(12):1560-1563
pubmed: 27742233
Free Radic Res. 2004 Oct;38(10):1133-42
pubmed: 15512802
Blood. 2010 Oct 7;116(14):2582-9
pubmed: 20554970
J Blood Med. 2015 Jun 17;6:197-209
pubmed: 26124688
Cytotherapy. 2006;8(4):315-7
pubmed: 16923606
Blood. 2011 May 12;117(19):5067-77
pubmed: 21415267
Biochim Biophys Acta. 2012 Sep;1823(9):1468-83
pubmed: 22610083
Nature. 2014 Jun 12;510(7504):235-240
pubmed: 24870228
Exp Hematol. 2002 Jan;30(1):42-8
pubmed: 11823036
Nat Cell Biol. 2003 Apr;5(4):336-40
pubmed: 12629548
J Cell Biochem. 2009 Oct 15;108(3):577-88
pubmed: 19650110
Adv Clin Exp Med. 2017 Aug;26(5):789-793
pubmed: 29068574
Cell. 2007 Oct 19;131(2):324-36
pubmed: 17956733
J Vis Exp. 2017 Aug 1;(126):
pubmed: 28809828
Blood Rev. 2008 Mar;22(2):53-63
pubmed: 18039551
Int J Mol Sci. 2017 Jan 13;18(1):
pubmed: 28098778
Ann N Y Acad Sci. 2005;1054:40-7
pubmed: 16339650
Sci Rep. 2015 May 13;5:10181
pubmed: 25970748
Blood. 2011 Sep 29;118(13):3479-88
pubmed: 21813448
Nat Rev Immunol. 2017 Sep;17(9):573-590
pubmed: 28604734
J Exp Clin Cancer Res. 2015 Aug 13;34:82
pubmed: 26264809
Expert Rev Mol Med. 2007 Dec 05;9(33):1-13
pubmed: 18053288
Nat Cell Biol. 2017 Mar;19(3):214-223
pubmed: 28218906
Handb Exp Pharmacol. 2006;(174):249-82
pubmed: 16370331
Science. 2004 Dec 17;306(5704):2090-3
pubmed: 15514116
Ann N Y Acad Sci. 2005;1054:186-95
pubmed: 16339665
Metabolism. 2018 Mar;80:66-79
pubmed: 28987275
Immunity. 2010 Sep 24;33(3):387-99
pubmed: 20850355
Curr Gene Ther. 2015;15(1):64-81
pubmed: 25429463
Cytotherapy. 2014 Jun;16(6):868-70
pubmed: 24631286
EMBO Mol Med. 2010 Aug;2(8):315-28
pubmed: 20665635
Cell Metab. 2005 Mar;1(3):191-200
pubmed: 16054062
Proc Natl Acad Sci U S A. 2008 Jul 29;105(30):10547-52
pubmed: 18650378
Cold Spring Harb Perspect Med. 2013 May 01;3(5):a011700
pubmed: 23637309
Int J Hematol. 2011 Jul;94(1):24-32
pubmed: 21567162
J Control Release. 2014 Oct 28;192:262-70
pubmed: 25084218
J Pediatr Hematol Oncol. 2011 Apr;33(3):179-84
pubmed: 21325969
PLoS One. 2015 Mar 16;10(3):e0120219
pubmed: 25774923
Hematology Am Soc Hematol Educ Program. 2010;2010:456-62
pubmed: 21239835
Biochim Biophys Acta. 2012 Sep;1823(9):1426-33
pubmed: 22440327
Stem Cell Reports. 2013 Jul 11;1(2):152-65
pubmed: 24052950
Cold Spring Harb Perspect Med. 2012 Sep 01;2(9):a011692
pubmed: 22951448
Ann N Y Acad Sci. 2016 Apr;1370(1):109-18
pubmed: 27270495
Oncotarget. 2017 Dec 30;9(3):4223-4238
pubmed: 29423117
Proc Natl Acad Sci U S A. 2001 Jul 3;98(14):7841-5
pubmed: 11427725
Nat Med. 2014 Aug;20(8):833-46
pubmed: 25100529
Nat Biotechnol. 2016 Jul 12;34(7):721-3
pubmed: 27404882
Oxid Med Cell Longev. 2016;2016:8629024
pubmed: 27006749
Immunity. 2006 Dec;25(6):977-88
pubmed: 17174120
Biochem Biophys Res Commun. 2018 Sep 3;503(1):297-303
pubmed: 29890135
J Stem Cells Regen Med. 2007 May 16;2(1):44
pubmed: 24692896