Skip to main content
SpringerLink
Log in

Efficacy and mechanisms underlying the effects of allogeneic umbilical cord mesenchymal stem cell transplantation on acute radiation injury in tree shrews

  • Published:
Cytotechnology Aims and scope Submit manuscript

Abstract

Umbilical cord mesenchymal stem cells (UC-MSCs) exert strong immunomodulatory effects and can repair organs. However, their roles in radiation injury remain unclear. We show that in tree shrews with acute radiation injury, injected UC-MSCs significantly improved survival rates, reduced lung inflammation and apoptosis, prevented pulmonary fibrotic processes, recovered hematopoiesis, and increased blood counts. A protein microarray analysis showed that serum levels of the anti-inflammatory cytokines IL-10 and IL-13 and the growth factors BMP-5, BMP-7, HGF, insulin, NT-4, VEGFR3, and SCF were significantly higher, while those of the inflammatory cytokines IL-2, TIMP-2, TNF-α, IFN-γ, IL-1ra, and IL-8 and the fibrosis-related factors PDGF-BB, PDGF-AA, TGF-β1, IGFBP-2, and IGFBP-4 were significantly lower in UC-MSC-injected animals. A transcriptome analysis of PBMCs showed that the mRNA expression of C1q was upregulated, while that of HLA-DP was downregulated after UC-MSC injection. These results confirm the immunohistochemistry results. eGFP-labeled UC-MSCs were traced in vivo and found in the heart, liver, spleen, lungs, kidneys, thymus, small intestine and bone marrow. Our findings suggest that UC-MSC transplantation may be a novel therapeutic approach for treating acute radiation injury.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  • Ao X, Lubman DM, Davis MA, Xing X, Kong FM, Lawrence TS, Zhang M (2008) Comparative proteomic analysis of radiation-induced changes in mouse lung: fibrosis-sensitive and -resistant strains. Radiat Res 169:417–425

    Article  CAS  Google Scholar 

  • Armbrust T, Nordmann B, Kreissig M, Ramadori G (1997) C1Q synthesis by tissue mononuclear phagocytes from normal and from damaged rat liver: up-regulation by dexamethasone, down-regulation by interferon gamma, and lipopolysaccharide. Hepatology 26:98–106

    CAS  PubMed  Google Scholar 

  • Arno AI, Amini-Nik S, Blit PH, Al-Shehab M, Belo C, Herer E, Tien CH, Jeschke MG (2014) Human Wharton’s jelly mesenchymal stem cells promote skin wound healing through paracrine signaling. Stem Cell Res Ther 5:28

    Article  Google Scholar 

  • Arrieta O, Gallardorincón D, Villarrealgarza C, Michel RM, Astorga-Ramos AM, Martínez-Barrera L, de la Garza J (2009) High frequency of radiation pneumonitis in patients with locally advanced non-small cell lung cancer treated with concurrent radiotherapy and gemcitabine after induction with gemcitabine and carboplatin. J Thorac Oncol 4:845–852

    Article  Google Scholar 

  • Chambers D (2015) Mesenchymal stromal cell-based therapies for lung disease. In: Bertoncello I, (ed) Stem cells in the lung. Development, repair and regeneration, Springer International Publishing, pp. 225–242

  • Cserhalmi M, Csincsi ÁI, Mezei Z, Kopp A, Hebecker M, Uzonyi B, Józsi M (2017) The murine factor H-related protein FHR-B promotes complement activation. Front Immunol 8:1145

    Article  Google Scholar 

  • Dietzschold B, Schwaeble W, Schäfer MK, Hooper DC, Zehng YM, Petry F, Sheng H, Fink T, Loos M, Koprowski H, Weihe E (1995) Expression of C1q, a subcomponent of the rat complement system, is dramatically enhanced in brains of rats with either Borna disease or experimental allergic encephalomyelitis. J Neurol Sci 130:11–16

    Article  CAS  Google Scholar 

  • Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop DJ, Horwitz E (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8:315–317

    Article  CAS  Google Scholar 

  • Fausto AKS, Silva TDF, Romanel E, Vaslin MFS (2017) microRNAs as reference genes for quantitative PCR in cotton. PLoS ONE 12:e0174722

    Article  Google Scholar 

  • Flechsig P, Dadrich M, Bickelhaupt S, Jenne J, Hauser K, Timke C, Peschke P, Hahn EW, Gröne HJ, Yingling J, Lahn M, Wirkner U, Huber PE (2012) LY2109761 attenuates radiation-induced pulmonary murine fibrosis via reversal of TGF-beta and BMP-associated proinflammatory and proangiogenic signals. Clin Cancer Res 18:3616–3627

    Article  CAS  Google Scholar 

  • Ghafoori P, Marks LB, Vujaskovic Z, Kelsey CR (2008) Radiation-induced lung injury. Assessment, management, and prevention. Assessment Manage Prev Oncol 22:37–47

    Google Scholar 

  • Giridhar P, Mallick S, Rath GK, Julka PK (2015) Radiation induced lung injury: prediction, assessment and management. Asian Pac J Cancer Prev 16:2613–2617

    Article  Google Scholar 

  • Gorbunov NV, Kiang JG (2017) Ghrelin therapy decreases incidents of intracranial hemorrhage in mice after whole-body ionizing irradiation combined with burn trauma. Int J Mol Sci 18(pii):E1693

    Article  Google Scholar 

  • Han DM, Wang ZD, Ding L, Zheng XL, Yan HM, Xue M, Zhu L, Liu J, Wang HX (2014) Effect of umbilical cord MSC infusion on the pulmonary infection in haploidentical hematopoietic stem cell transplantation. J Exp Hematol 22:1084–1088

    Google Scholar 

  • Ho MM, Manughian-Peter A, Spivia WR, Taylor A, Fraser DA (2016) Macrophage molecular signaling and inflammatory responses during ingestion of atherogenic lipoproteins are modulated by complement protein C1q. Atherosclerosis 253:38–46

    Article  CAS  Google Scholar 

  • Hulsebus HJ, O’Conner SD, Smith EM, Jie C, Bohlson SS (2016) Complement component C1q programs a pro-efferocytic phenotype while limiting TNFα production in primary mouse and human macrophages. Front Immunol 7:230

    Article  Google Scholar 

  • Inga Jácome MC, Morales Chacòn LM, Vera Cuesta H, Maragoto Rizo C, Whilby Santiesteban M, Ramos Hernandez L, Noris García E, González Fraguela ME, Fernandez Verdecia CI, Vegas Hurtado Y, Siniscalco D, Gonçalves CA, Robinson-Agramonte ML (2016) Peripheral inflammatory markers contributing to comorbidities in autism. Behav Sci 6(pii):E29

    Article  Google Scholar 

  • Johnson LA, June CH (2017) Driving gene-engineered T cell immunotherapy of cancer. Cell Res 27:38–58

    Article  CAS  Google Scholar 

  • Kaul M, Loos M (1995) Collagen-like complement component C1q is a membrane protein of human monocyte-derived macrophages that mediates endocytosis. J Immunol 155:5795–5802

    CAS  PubMed  Google Scholar 

  • Kaur A, Sultan SH, Murugaiah V, Pathan AA, Alhamlan FS, Karteris E, Kishore U (2016) Human c1q induces apoptosis in an ovarian cancer cell lineviatumor necrosis factor pathway. Front Immunol 7:599

    Article  Google Scholar 

  • Kolev M, Le FG, Kemper C (2014) Complement–tapping into new sites and effector systems. Nat Rev Immunol 14:811–820

    Article  CAS  Google Scholar 

  • Li M, Verena J, Claus B (2007) The role of PDGF in radiation oncology. Radiat Onco 12:1–9

    CAS  Google Scholar 

  • Li T, Xia M, Gao Y, Chen Y, Xu Y (2015) Human umbilical cord mesenchymal stem cells: an overview of their potential in cell-based therapy. Expert Opin Biol Ther 15:1–14

    Article  Google Scholar 

  • Li C, Xu D, Ye Q, Hong S, Jiang Y, Liu X, Zhang N, Shi L, Qin CF, Xu Z (2016) Zika virus disrupts neural progenitor development and leads to microcephaly in mice. Cell Stem Cell 19:120–126

    Article  CAS  Google Scholar 

  • Li X, Ma D, Zha X, Quan D, Pan D, Sun M, Hu B, Zhao B (2017) Ilomastat, a synthetic inhibitor of MMPs, prevents lung injury induced by γ-ray irradiation in mice. Oncotarget 8:60789

    PubMed  PubMed Central  Google Scholar 

  • Majeed T (2017) Mitigation of whole-body gamma radiation-induced damages by Clerodendron infortunatum in mammalian organisms. J Radiat Res 58:281–291

    PubMed  Google Scholar 

  • Marupanthorn K, Tantrawatpan C, Kheolamai P, Tantikanlayaporn D, Manochantr S (2017) Bone morphogenetic protein-2 enhances the osteogenic differentiation capacity of mesenchymal stromal cells derived from human bone marrow and umbilical cord. Int J Mol Med 39:654–662

    Article  CAS  Google Scholar 

  • Pan XH, Huang X, Ruan GP, Pang RQ, Chen Q, Wang JX, He J, Zhao J, Cai XM, Zhao N, Chen Y, Zhu XQ (2017) Umbilical cord mesenchymal stem cells are able to undergo differentiation into functional islet-like cells in type 2 diabetic tree shrews. Mol Cell Probes 34:1–12

    Article  CAS  Google Scholar 

  • Pasi F, Paolini A, Nano R, Di Liberto R, Capelli E (2014) Effects of single or combined treatments with radiation and chemotherapy on survival and danger signals expression in glioblastoma cell lines. Biomed Res Int 2014:453–497

    Article  Google Scholar 

  • Phinney DG, Prockop DJ (2007) Concise review: mesenchymal stem/multipotent stromal cells: the state of transdifferentiation and modes of tissue repair-current views. Stem Cells 25:2896–2902

    Article  Google Scholar 

  • Pulanco MC, Cosman J, Ho MM, Huynh J, Fing K, Turcu J, Fraser DA (2016) Complement protein C1q enhances macrophage foam cell survival and efferocytosis. J Immunol 198:472–480

    Article  Google Scholar 

  • Ricklin D, Reis ES, Lambris JD (2016) Complement in disease: a defence system turning offensive. Nat Rev Nephrol 12:383–401

    Article  CAS  Google Scholar 

  • Schwaeble W, Schäfer MK, Petry F, Fink T, Knebel D, Weihe E, Loos M (1995) Follicular dendritic cells, interdigitating cells, and cells of the monocyte-macrophage lineage are the C1q-producing sources in the spleen. Identification of specific cell types by in situ hybridization and immunohistochemical analysis. J Immunol 155:4971–4978

    CAS  PubMed  Google Scholar 

  • Singhrao SK, Neal JW, Morgan BP, Gasque P (1999) Increased complement biosynthesis by microglia and complement activation on neurons in Huntington’s disease. Exp Neurol 159:362–378

    Article  CAS  Google Scholar 

  • Spivia W, Magno PS, Le P, Fraser DA (2014) Complement protein C1q promotes macrophage anti-inflammatory M2-like polarization during the clearance of atherogenic lipoproteins. Inflamm Res 63:885–893

    Article  CAS  Google Scholar 

  • Stegert M, Bock M, Trendelenburg M (2015) Clinical presentation of human C1q deficiency: How much of a lupus? Mol Immunol 67:3–11

    Article  CAS  Google Scholar 

  • Sun L, Zhang H, Bi L, Shi YF, Xing C, Tang L, Jiang S, Yu K (2016) Angiopoietin-1 facilitates recovery of hematopoiesis in radiated mice. Am J Transl Res 8:2011–2021

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wei L, Zhang J, Xiao XB, Mai HX, Zheng K, Sun WL, Wang L, Liang F, Yang ZL, Liu Y, Wang YQ, Li ZF, Wang JN, Zhang WJ, You H (2014) Multiple injections of human umbilical cord-derived mesenchymal stromal cells through the tail vein improve microcirculation and the microenvironment in a rat model of radiation myelopathy. J Transl Med 12:246

    Article  Google Scholar 

  • Willems S, Verleden SE, Vanaudenaerde BM, Wynants M, Dooms C, Yserbyt J, Somers J, Verbeken EK, Verleden GM, Wuyts WA (2013) Multiplex protein profiling of bronchoalveolar lavage in idiopathic pulmonary fibrosis and hypersensitivity pneumonitis. Ann Thorac Med 8:38–45

    Article  CAS  Google Scholar 

  • Zhang MJ, Sun JJ, Qian L, Liu Z, Zhang Z, Cao W, Li W, Xu Y (2011) Human umbilical mesenchymal stem cells enhance the expression of neurotrophic factors and protect ataxic mice. Brain Research 1402:122–131

    Article  CAS  Google Scholar 

  • Zhou AQ, Herriott MJ, Leu RW (1991) Kinetics of the biosynthesis of complement subcomponent C1q by murine macrophages: LPS, immune complexes, and zymosan alone and in combination with interferon-gamma. J Leukoc Biol 50:453–463

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by funding from the Key Program of Kunming (No. 2015-1-S-00973), the National Natural Science Foundation of China (No. 31660655), and Applied Basic Research of Yunnan Province (Nos. 2016FB146, 2017FB042 and 2015FA039).

Author information

Authors and Affiliations

  1. Department of Clinical Laboratory, Kunming General Hospital, Army Medical University, Kunming, 650032, Yunnan Province, China

    De-Bin Guo, Xiang-Qing Zhu, Gao-Mi-Yang Liu, Guang-Ping Ruan, Rong-Qing Pang, Qiang Wang, Jin-Xiang Wang & Xing-Hua Pan

  2. Cell Biological Therapy Center of Kunming General Hospital of Chengdu Military Command, Kunming, Yunnan Province, China

    Xiang-Qing Zhu, Gao-Mi-Yang Liu, Guang-Ping Ruan, Rong-Qing Pang, Qiang Wang, Jin-Xiang Wang, Ju-Fen Liu & Xing-Hua Pan

  3. Kunming Medical University, Kunming, Yunnan Province, China

    Qing-Qing Li

  4. Guizhou Medical University, Guiyang, Guizhou Province, China

    Yu-Hao Chen

  5. Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, 650093, Yunnan Province, China

    Qiang Chen

Authors
  1. De-Bin Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiang-Qing Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qing-Qing Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gao-Mi-Yang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Guang-Ping Ruan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rong-Qing Pang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yu-Hao Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Qiang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jin-Xiang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ju-Fen Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Qiang Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Xing-Hua Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

DBG, XQZ and XHP designed the study and wrote the paper; QQL and GMYL participated in the RT-PCR and flow cytometric analyses; GPR carried out the statistical analysis of the data; RQP, YHC and QW established the acute radiation injury model in the tree shrews and completed the UC-MSC transplantations; and JXW, JFL and QC cultured and labeled UC-MSCs.

Corresponding author

Correspondence to Xing-Hua Pan.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Ethical approval and consent to participate

All experimental protocols were approved by the Experimental Animal Ethics Committee of Kunming General Hospital [Approval number (fast): 2,014,013].

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guo, DB., Zhu, XQ., Li, QQ. et al. Efficacy and mechanisms underlying the effects of allogeneic umbilical cord mesenchymal stem cell transplantation on acute radiation injury in tree shrews. Cytotechnology 70, 1447–1468 (2018). https://doi.org/10.1007/s10616-018-0239-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10616-018-0239-z

Keywords

Search

Navigation