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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2018

Open Access 01-12-2018 | Research

Splenic involvement in umbilical cord matrix-derived mesenchymal stromal cell-mediated effects following traumatic spinal cord injury

Authors: Anna Badner, Justin Hacker, James Hong, Mirriam Mikhail, Reaz Vawda, Michael G. Fehlings

Published in: Journal of Neuroinflammation | Issue 1/2018

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Abstract

Background

The spleen plays an important role in erythrocyte turnover, adaptive immunity, antibody production, and the mobilization of monocytes/macrophages (Mφ) following tissue injury. In response to trauma, the spleen initiates production of inflammatory cytokines, which in turn recruit immune cells to the inflamed tissue, exacerbating damage. Our previous work has shown that intravenous mesenchymal stromal cell (MSC) infusion has potent immunomodulatory effects following spinal cord injury (SCI), associated with the transplanted cells homing to and persisting within the spleen. Therefore, this work aimed to characterize the relationship between the splenic inflammatory response and SCI pathophysiology, emphasizing splenic involvement in MSC-mediated effects.

Methods

Using a rodent model of cervical clip-compression SCI, secondary tissue damage and functional recovery were compared between splenectomised rodents and those with a sham procedure. Subsequently, 2.5 million MSCs from the term human umbilical cord matrix cells (HUCMCs) were infused via tail vein at 1-h post-SCI and the effects were assessed in the presence or absence of a spleen.

Results

Splenectomy alone had no effect on lesion volume, hemorrhage, or inflammation. There was also no significant difference between the groups in functional recovery and those in lesion morphometry. Yet, while the infusion of HUCMCs reduced spinal cord hemorrhage and increased systemic levels of IL-10 in the presence of a spleen, these effects were lost with splenectomy. Further, HUCMC infusion was shown to alter the expression levels of splenic cytokines, suggesting that the spleen is an important target and site of MSC effects.

Conclusions

Our results provide a link between MSC function and splenic inflammation, a finding that can help tailor the cells/transplantation approach to enhance therapeutic efficacy.
Appendix
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Literature
1.
Ulndreaj A, Badner A, Fehlings MG. Promising neuroprotective strategies for traumatic spinal cord injury with a focus on the differential effects among anatomical levels of injury. F1000Res. 2017;6:1907.CrossRefPubMedPubMedCentral
2.
Tator CH, Fehlings MG. Review of the secondary injury theory of acute spinal cord trauma with emphasis on vascular mechanisms. J Neurosurg. 1991;75:15–26.CrossRefPubMed
3.
4.
Jung W-C, Levesque J-P, Ruitenberg MJ. It takes nerve to fight back: the significance of neural innervation of the bone marrow and spleen for immune function. Semin Cell Dev Biol. 2016.
5.
Lucin KM, Sanders VM, Jones TB, Malarkey WB, Popovich PG. Impaired antibody synthesis after spinal cord injury is level dependent and is due to sympathetic nervous system dysregulation. Exp Neurol. 2007;207:75–84.CrossRefPubMedPubMedCentral
6.
Brommer B, Engel O, Kopp MA, Watzlawick R, Müller S, Prüss H, et al. Spinal cord injury-induced immune deficiency syndrome enhances infection susceptibility dependent on lesion level. Brain J Neurol. 2016;139:692–707.CrossRef
7.
Ueno M, Ueno-Nakamura Y, Niehaus J, Popovich PG, Yoshida Y. Silencing spinal interneurons inhibits immune suppressive autonomic reflexes caused by spinal cord injury. Nat Neurosci. 2016;19:784–7.CrossRefPubMedPubMedCentral
8.
Ulndreaj A, Tzekou A, Mothe AJ, Siddiqui AM, Dragas R, Tator CH, et al. Characterization of the antibody response after cervical spinal cord injury. J Neurotrauma. 2017;34:1209–26.CrossRefPubMedPubMedCentral
9.
Swirski FK, Nahrendorf M, Etzrodt M, Wildgruber M, Cortez-Retamozo V, Panizzi P, et al. Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science. 2009;325:612–6.CrossRefPubMedPubMedCentral
10.
Ajmo CT, Vernon DOL, Collier L, Hall AA, Garbuzova-Davis S, Willing A, et al. The spleen contributes to stroke-induced neurodegeneration. J Neurosci Res. 2008;86:2227–34.CrossRefPubMedPubMedCentral
11.
12.
Seifert HA, Hall AA, Chapman CB, Collier LA, Willing AE, Pennypacker KR. A transient decrease in spleen size following stroke corresponds to splenocyte release into systemic circulation. J Neuroimmune Pharmacol Off J Soc NeuroImmune Pharmacol. 2012;7:1017–24.CrossRef
13.
Zhang Y, Guan Z, Reader B, Shawler T, Mandrekar-Colucci S, Huang K, et al. Autonomic dysreflexia causes chronic immune suppression after spinal cord injury. J Neurosci. 2013;33:12970–81.CrossRefPubMedPubMedCentral
14.
Blomster LV, Brennan FH, Lao HW, Harle DW, Harvey AR, Ruitenberg MJ. Mobilisation of the splenic monocyte reservoir and peripheral CX3 CR1 deficiency adversely affects recovery from spinal cord injury. Exp Neurol. 2013;247:226–40.CrossRefPubMed
15.
Kim E, Yang J, Beltran CD, Cho S. Role of spleen-derived monocytes/macrophages in acute ischemic brain injury. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab. 2014;34:1411–9.CrossRef
16.
17.
Acosta SA, Tajiri N, Hoover J, Kaneko Y, Borlongan CV. Intravenous bone marrow stem cell grafts preferentially migrate to spleen and abrogate chronic inflammation in stroke. Stroke. 2015;46:2616–27.CrossRefPubMedPubMedCentral
18.
Yang B, Hamilton JA, Valenzuela KS, Bogaerts A, Aronowski J, Mays RW, et al. Multipotent adult progenitor cells enhance recovery after stroke by modulating the immune response from the spleen. Stem Cells Dayt Ohio. 2017;35:1290–302.CrossRef
19.
Menge T, Zhao Y, Zhao J, Wataha K, Gerber M, Zhang J, et al. Mesenchymal stem cells regulate blood-brain barrier integrity through TIMP3 release after traumatic brain injury. Sci Transl Med. 2012;4:161ra150.CrossRefPubMedPubMedCentral
20.
Walker PA, Shah SK, Jimenez F, Gerber MH, Xue H, Cutrone R, et al. Intravenous multipotent adult progenitor cell therapy for traumatic brain injury: preserving the blood brain barrier via an interaction with splenocytes. Exp Neurol. 2010;225:341–52.CrossRefPubMedPubMedCentral
21.
DePaul MA, Palmer M, Lang BT, Cutrone R, Tran AP, Madalena KM, et al. Intravenous multipotent adult progenitor cell treatment decreases inflammation leading to functional recovery following spinal cord injury. Sci Rep. 2015;5:16795.CrossRefPubMedPubMedCentral
22.
Badner A, Vawda R, Laliberte A, Hong J, Mikhail M, Jose A, et al. Early intravenous delivery of human brain stromal cells modulates systemic inflammation and leads to vasoprotection in traumatic spinal cord injury. Stem Cells Transl Med. 2016;5:991–1003.CrossRefPubMedPubMedCentral
23.
Fabian C, Naaldijk Y, Leovsky C, Johnson AA, Rudolph L, Jaeger C, et al. Distribution pattern following systemic mesenchymal stem cell injection depends on the age of the recipient and neuronal health. Stem Cell Res Ther. 2017;8:85.CrossRefPubMedPubMedCentral
24.
Soubeyrand M, Badner A, Vawda R, Chung YS, Fehlings MG. Very high resolution ultrasound imaging for real-time quantitative visualization of vascular disruption after spinal cord injury. J Neurotrauma. 2014;31:1767–75.CrossRefPubMedPubMedCentral
25.
Choudhri TF, Hoh BL, Solomon RA, Connolly ES, Pinsky DJ. Use of a spectrophotometric hemoglobin assay to objectively quantify intracerebral hemorrhage in mice. Stroke. 1997;28:2296–302.CrossRefPubMed
26.
Forgione N, Karadimas SK, Foltz WD, Satkunendrarajah K, Lip A, Fehlings MG. Bilateral contusion-compression model of incomplete traumatic cervical spinal cord injury. J Neurotrauma. 2014;31:1776–88.CrossRefPubMedPubMedCentral
27.
Rivlin AS, Tator CH. Objective clinical assessment of motor function after experimental spinal cord injury in the rat. J Neurosurg. 1977;47:577–81.CrossRefPubMed
28.
Basso DM, Beattie MS, Bresnahan JC. A sensitive and reliable locomotor rating scale for open field testing in rats. J Neurotrauma. 1995;12:1–21.CrossRefPubMed
29.
Nguyen DH, Cho N, Satkunendrarajah K, Austin JW, Wang J, Fehlings MG. Immunoglobulin G (IgG) attenuates neuroinflammation and improves neurobehavioral recovery after cervical spinal cord injury. J Neuroinflammation. 2012;9:224.CrossRefPubMedPubMedCentral
30.
Sun X, Jones ZB, Chen X-M, Zhou L, So K-F, Ren Y. Multiple organ dysfunction and systemic inflammation after spinal cord injury: a complex relationship. J Neuroinflammation. 2016;13:260.CrossRefPubMedPubMedCentral
31.
Lankford KL, Arroyo EJ, Nazimek K, Bryniarski K, Askenase PW, Kocsis JD. Intravenously delivered mesenchymal stem cell-derived exosomes target M2-type macrophages in the injured spinal cord. PLoS One. 2018;13:e0190358.CrossRefPubMedPubMedCentral
32.
Seeley EJ, Barry SS, Narala S, Matthay MA, Wolters PJ. Noradrenergic neurons regulate monocyte trafficking and mortality during gram-negative peritonitis in mice. J Immunol Baltim Md 1950. 2013;190:4717–24.
33.
Cortez-Retamozo V, Etzrodt M, Newton A, Rauch PJ, Chudnovskiy A, Berger C, et al. Origins of tumor-associated macrophages and neutrophils. Proc Natl Acad Sci U S A. 2012;109:2491–6.CrossRefPubMedPubMedCentral
34.
Baud V, Karin M. Signal transduction by tumor necrosis factor and its relatives. Trends Cell Biol. 2001;11:372–7.CrossRefPubMed
35.
Lee RH, Pulin AA, Seo MJ, Kota DJ, Ylostalo J, Larson BL, et al. Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell. 2009;5:54–63.CrossRefPubMedPubMedCentral
36.
Choi H, Lee RH, Bazhanov N, Oh JY, Prockop DJ. Anti-inflammatory protein TSG-6 secreted by activated MSCs attenuates zymosan-induced mouse peritonitis by decreasing TLR2/NF-κB signaling in resident macrophages. Blood. 2011;118:330–8.CrossRefPubMedPubMedCentral
37.
Lee RH, Yu JM, Foskett AM, Peltier G, Reneau JC, Bazhanov N, et al. TSG-6 as a biomarker to predict efficacy of human mesenchymal stem/progenitor cells (hMSCs) in modulating sterile inflammation in vivo. Proc Natl Acad Sci U S A. 2014;111:16766–71.CrossRefPubMedPubMedCentral
38.
Hamidian Jahromi S, Li Y, Davies JE. Effect of Tumor Necrosis Factor Alpha Dose and Exposure Time on Tumor Necrosis Factor-Induced Gene-6 Activation by Neonatal and Adult Mesenchymal Stromal Cells. Stem Cells Dev. 2018;27(1):44-54. https://​doi.​org/​10.​1089/​scd.​2017.​0179.
39.
Song W-J, Li Q, Ryu M-O, Ahn J-O, Ha Bhang D, Chan Jung Y, et al. TSG-6 secreted by human adipose tissue-derived mesenchymal stem cells ameliorates DSS-induced colitis by inducing M2 macrophage polarization in mice. Sci Rep. 2017;7:5187.CrossRefPubMedPubMedCentral
40.
Mittal M, Tiruppathi C, Nepal S, Zhao Y-Y, Grzych D, Soni D, et al. TNFα-stimulated gene-6 (TSG6) activates macrophage phenotype transition to prevent inflammatory lung injury. Proc Natl Acad Sci U S A. 2016;113:E8151–8.CrossRefPubMedPubMedCentral
41.
42.
Shechter R, London A, Varol C, Raposo C, Cusimano M, Yovel G, et al. Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice. PLoS Med. 2009;6:e1000113.CrossRefPubMedPubMedCentral
43.
Kigerl KA, Gensel JC, Ankeny DP, Alexander JK, Donnelly DJ, Popovich PG. Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Neurosci. 2009;29:13435–44.CrossRefPubMedPubMedCentral
44.
45.
McTigue DM, Tripathi R, Wei P, Lash AT. The PPAR gamma agonist Pioglitazone improves anatomical and locomotor recovery after rodent spinal cord injury. Exp Neurol. 2007;205:396–406.CrossRefPubMedPubMedCentral
46.
White SV, Czisch CE, Han MH, Plant CD, Harvey AR, Plant GW. Intravenous transplantation of mesenchymal progenitors distribute solely to the lungs and improve outcomes in cervical spinal cord injury. Stem Cells Dayt Ohio. 2016;34:1812–25.CrossRef
47.
48.
49.
50.
Leuschner F, Dutta P, Gorbatov R, Novobrantseva TI, Donahoe JS, Courties G, et al. Therapeutic siRNA silencing in inflammatory monocytes in mice. Nat Biotechnol. 2011;29:1005–10.CrossRefPubMedPubMedCentral
51.
52.
Cortez-Retamozo V, Etzrodt M, Newton A, Ryan R, Pucci F, Sio SW, et al. Angiotensin II drives the production of tumor-promoting macrophages. Immunity. 2013;38:296–308.CrossRefPubMedPubMedCentral
53.
Lozito TP, Kuo CK, Taboas JM, Tuan RS. Human mesenchymal stem cells express vascular cell phenotypes upon interaction with endothelial cell matrix. J Cell Biochem. 2009;107:714–22.CrossRefPubMedPubMedCentral
54.
Menge T, Gerber M, Wataha K, Reid W, Guha S, Cox CS, et al. Human mesenchymal stem cells inhibit endothelial proliferation and angiogenesis via cell-cell contact through modulation of the VE-cadherin/β-catenin signaling pathway. Stem Cells Dev. 2013;22:148–57.CrossRefPubMed
55.
Zhao Y, Gibb SL, Zhao J, Moore AN, Hylin MJ, Menge T, et al. Wnt3a, a protein secreted by mesenchymal stem cells is neuroprotective and promotes neurocognitive recovery following traumatic brain injury. Stem Cells Dayt Ohio. 2016;34:1263–72.CrossRef
56.
Vasandan AB, Jahnavi S, Shashank C, Prasad P, Kumar A, Prasanna SJ. Human mesenchymal stem cells program macrophage plasticity by altering their metabolic status via a PGE2-dependent mechanism. Sci Rep. 2016;6:38308.CrossRefPubMedPubMedCentral
Metadata
Title
Splenic involvement in umbilical cord matrix-derived mesenchymal stromal cell-mediated effects following traumatic spinal cord injury
Authors
Anna Badner
Justin Hacker
James Hong
Mirriam Mikhail
Reaz Vawda
Michael G. Fehlings
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2018
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-018-1243-0

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