CCL1 blockade alleviates human mesenchymal stem cell (hMSC)-induced pulmonary fibrosis in a murine sclerodermatous graft-versus-host disease (Scl-GVHD) model.
Allogeneic hematopoietic stem cell transplantation
Chronic graft-versus-host disease
Mesenchymal stem cells
Sclerodermatous graft-versus-host disease
Journal
Stem cell research & therapy
ISSN: 1757-6512
Titre abrégé: Stem Cell Res Ther
Pays: England
ID NLM: 101527581
Informations de publication
Date de publication:
26 06 2020
26 06 2020
Historique:
received:
26
03
2020
accepted:
11
06
2020
revised:
07
05
2020
entrez:
27
6
2020
pubmed:
27
6
2020
medline:
22
6
2021
Statut:
epublish
Résumé
Human chronic graft-versus-host disease (CGVHD) shares clinical characteristics with a murine sclerodermatous GVHD (Scl-GVHD, B10.D2 → BALB/c) model that is characterized by skin and lung fibrosis. In this study, bone marrow- or adipose tissue-derived human mesenchymal stem cells (hMSCs) were injected into the Scl-GVHD mice to address their therapeutic effect on CGVHD. Lethally irradiated BALB/c mice were transplanted with B10.D2 T cell-depleted bone marrow with or without spleen cells to generate Scl-GVHD. hMSCs were intravenously treated on days 3, 5, and 7 post-transplantation, and the control antibody or CCL1 blocking antibody was subcutaneously injected according to the same schedule as the hMSCs. Fourteen days after transplantation, the recipient mice were sacrificed, and their skin and lungs were analyzed. After the early injection of hMSCs after transplantation, the clinical and pathological severity of Scl-GVHD in the skin was significantly attenuated, whereas the pathological score was exacerbated in the lungs. hMSCs had migrated into the lungs, but not into the skin. CD11b monocyte/macrophages and CD4 T cells were markedly decreased in skin tissues, whereas there was an early recruitment of CD11b cells, and subsequently increased infiltration of CD4 T cells, in the lungs. Importantly, hMSCs persistently upregulated the expression of CCL1 in the lungs, but not in the skin. Concurrent treatment of hMSCs with a CCL1-blocking antibody alleviated the severity of the lung histopathology score and fibrosis with the preservation of the cutaneous protective effect against CGVHD. Infiltration of CD3 T cells and CD68 macrophages and upregulation of chemokines were also decreased in lung tissues, along with the recruitment of eosinophils and tissue IgE expression. In the skin, chemokine expression was further reduced after CCL1 blockade. These data demonstrate that despite a protective effect against Scl-GVHD in the skin, administration of hMSCs exacerbated lung fibrosis associated with eosinophilia and airway inflammation through persistent CCL1 upregulation. CCL1 blockade offers a potential treatment of pulmonary complications induced after treatment with hMSCs.
Sections du résumé
BACKGROUND
Human chronic graft-versus-host disease (CGVHD) shares clinical characteristics with a murine sclerodermatous GVHD (Scl-GVHD, B10.D2 → BALB/c) model that is characterized by skin and lung fibrosis. In this study, bone marrow- or adipose tissue-derived human mesenchymal stem cells (hMSCs) were injected into the Scl-GVHD mice to address their therapeutic effect on CGVHD.
METHODS
Lethally irradiated BALB/c mice were transplanted with B10.D2 T cell-depleted bone marrow with or without spleen cells to generate Scl-GVHD. hMSCs were intravenously treated on days 3, 5, and 7 post-transplantation, and the control antibody or CCL1 blocking antibody was subcutaneously injected according to the same schedule as the hMSCs. Fourteen days after transplantation, the recipient mice were sacrificed, and their skin and lungs were analyzed.
RESULTS
After the early injection of hMSCs after transplantation, the clinical and pathological severity of Scl-GVHD in the skin was significantly attenuated, whereas the pathological score was exacerbated in the lungs. hMSCs had migrated into the lungs, but not into the skin. CD11b monocyte/macrophages and CD4 T cells were markedly decreased in skin tissues, whereas there was an early recruitment of CD11b cells, and subsequently increased infiltration of CD4 T cells, in the lungs. Importantly, hMSCs persistently upregulated the expression of CCL1 in the lungs, but not in the skin. Concurrent treatment of hMSCs with a CCL1-blocking antibody alleviated the severity of the lung histopathology score and fibrosis with the preservation of the cutaneous protective effect against CGVHD. Infiltration of CD3 T cells and CD68 macrophages and upregulation of chemokines were also decreased in lung tissues, along with the recruitment of eosinophils and tissue IgE expression. In the skin, chemokine expression was further reduced after CCL1 blockade.
CONCLUSIONS
These data demonstrate that despite a protective effect against Scl-GVHD in the skin, administration of hMSCs exacerbated lung fibrosis associated with eosinophilia and airway inflammation through persistent CCL1 upregulation. CCL1 blockade offers a potential treatment of pulmonary complications induced after treatment with hMSCs.
Identifiants
pubmed: 32586381
doi: 10.1186/s13287-020-01768-7
pii: 10.1186/s13287-020-01768-7
pmc: PMC7318460
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
254Références
Immunol Cell Biol. 2013 Jan;91(1):19-26
pubmed: 23090487
Xenotransplantation. 2012 Sep-Oct;19(5):273-85
pubmed: 22978461
Biol Blood Marrow Transplant. 2005 Dec;11(12):945-56
pubmed: 16338616
Arch Dermatol. 2002 Jul;138(7):924-34
pubmed: 12071820
Respir Res. 2018 Jun 8;19(1):113
pubmed: 29879991
Biol Blood Marrow Transplant. 2005 May;11(5):321-34
pubmed: 15846285
Am J Physiol Lung Cell Mol Physiol. 2015 Apr 1;308(7):L603-18
pubmed: 25637606
J Dermatol. 2010 Jan;37(1):26-41
pubmed: 20175838
Blood. 2015 Jan 22;125(4):606-15
pubmed: 25398933
Immunol Invest. 2014;43(1):41-53
pubmed: 24111544
J Dermatol Sci. 2014 Jun;74(3):214-21
pubmed: 24679982
Blood. 2001 Jan 15;97(2):367-75
pubmed: 11154210
PLoS One. 2012;7(10):e47559
pubmed: 23133515
Dis Model Mech. 2011 May;4(3):318-33
pubmed: 21558065
J Immunol. 2002 Mar 15;168(6):3088-98
pubmed: 11884483
J Immunol. 2001 Feb 1;166(3):2055-62
pubmed: 11160256
Arthritis Res Ther. 2010;12(2):R73
pubmed: 20429888
Leukemia. 2007 Aug;21(8):1733-8
pubmed: 17541394
J Immunol. 2003 May 1;170(9):4810-7
pubmed: 12707363
Annu Rev Immunol. 2014;32:659-702
pubmed: 24655300
Exp Lung Res. 2011 Apr;37(3):162-74
pubmed: 21269063
Nucl Med Biol. 2011 Oct;38(7):961-7
pubmed: 21810549
Nature. 2010 Aug 12;466(7308):829-34
pubmed: 20703299
Leukemia. 2009 Jan;23(1):78-84
pubmed: 18830253
Cell Immunol. 1983 Apr 1;77(1):1-12
pubmed: 6220812
Front Pharmacol. 2012 Feb 24;3:23
pubmed: 22375119
J Immunol. 1999 Nov 15;163(10):5693-9
pubmed: 10553100
J Immunol. 1999 Jul 1;163(1):403-11
pubmed: 10384142
Blood. 2002 Jul 15;100(2):415-9
pubmed: 12091330
J Immunol. 2011 Jun 15;186(12):7232-42
pubmed: 21576506
Lancet. 2008 May 10;371(9624):1579-86
pubmed: 18468541
Biochem Soc Trans. 2007 Aug;35(Pt 4):661-4
pubmed: 17635115
Nat Immunol. 2008 Sep;9(9):960-9
pubmed: 18711433
J Immunol. 2005 Feb 15;174(4):1962-70
pubmed: 15699124
Cytotherapy. 2006;8(4):315-7
pubmed: 16923606
Curr Opin Pharmacol. 2003 Aug;3(4):443-8
pubmed: 12901955
J Cell Biol. 1997 Jun 16;137(6):1445-57
pubmed: 9182674
Cell Transplant. 2010;19(6):667-79
pubmed: 20525442
Bone Marrow Transplant. 2002 Jun;29(12):979-86
pubmed: 12098066
Stem Cells Dev. 2013 Nov 1;22(21):2825-35
pubmed: 23767885
J Invest Dermatol. 2017 Sep;137(9):1895-1904
pubmed: 28526296
Cell Transplant. 2009;18(12):1369-79
pubmed: 19849895
J Clin Invest. 2003 Jul;112(1):101-8
pubmed: 12840064
J Immunol. 2006 Nov 15;177(10):6940-51
pubmed: 17082609
J Immunol. 2000 Apr 15;164(8):4048-54
pubmed: 10754297