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K. Xu et al.
the standpoint of basic science, the observation of trans- planted human stem cells within the lymphatic vessels and adjacent to inflammatory cells in the brain, but sur- prisingly also in the spleen, reveals for the first time the migration of intracerebrally infused stem cells to the periphery. From a translational research view, the visuali- zation of transplanted stem cells within lymphatic vessels and CD68-positive stem cells phagocytosing apoptotic neurons in the brain and spleen may correspond to a novel clean-up machinery of stem cells designed to dampen the stroke brain’s overload of cell death components and sig- nals, scuttling them from the central nervous system to the periphery. Altogether, our observations indicate that stem cells are capable of phagocytic activity centrally and peripherally, likely designed to sequester and remove inflammatory cells and dying neurons from the brain and dump them in the periphery, and suggest a therapeutic mechanism involving central and peripheral sequestration of stroke inflammation. Moreover, the observed hBMSC
migration patterns indicate the central role of the spleen in stroke pathology and reaffirm the importance of inflam- matory signaling in stem cell migration. This study resolves the apparent paradox of robust functional recov- ery seen after stem cell transplantation in stroke despite minimal graft survival rates.
In summary, we demonstrate here that intracerebrally transplanted stem cells exhibit the ability to migrate from the brain parenchyma to the spleen via lymphatic vessels, led by inflammatory signals. Describing the migratory patterns and biodistribution of stem cells following trans- plantation furthers our understanding of how these cells offer their therapeutic effects as well as enhancing our knowledge of the spleen and lymphatic system’s involve- ment in stroke pathology.
Acknowledgments
This work was supported by NIH grants 5R01-NS090962- 01 to CVB and NIH 1RONS102395-0 to CVB.
References
1. Kim AS, Cahill E, Cheng NT. Global stroke belt: geographic variation in stroke burden worldwide. Stroke. 2015;46(12):3564-3570.
2. Gopurappilly R, Pal R, Mamidi MK, Dey S, Bhonde R, Das AK. Stem cells in stroke repair: current success and future prospects. CNS Neurol Disord Drug Targets. 2011;10(6):741-756.
3. Liska MG, Crowley MG, Borlongan CV. Regulated and unregulated clinical trials of stem cell therapies for stroke. Transl Stroke Res. 2017;8(2):93-103.
4. Moskowitz MA, Lo EH, Iadecola C. The sci- ence of stroke: mechanisms in search of treatments. Neuron. 2010;67(2):181-198.
5. Macrez R, Ali C, Toutirais O, et al. Stroke and the immune system: from pathophysi- ology to new therapeutic strategies. Lancet Neurol. 2011;10(5):471-480.
6. Yong VW, Rivest S. Taking advantage of the systemic immune system to cure brain dis- eases. Neuron. 2009;64(1):55-60.
7. Jin R, Yang G, Li G. Inflammatory mecha- nisms in ischemic stroke: role of inflamma- tory cells. J Leukoc Biol. 2010;87(5):779-789.
8. Denes A, Ferenczi S, Kovacs KJ. Systemic inflammatory challenges compromise sur- vival after experimental stroke via augment- ing brain inflammation, blood-brain barrier damage and brain oedema independently of infarct size. J Neuroinflammation. 2011; 8:164.
9. Kassner A, Merali Z. Assessment of blood- brain barrier disruption in stroke. Stroke. 2015;46(11):3310-3315.
10. McColl BW, Rothwell NJ, Allan SM. Systemic inflammation alters the kinetics of cerebrovascular tight junction disruption after experimental stroke in mice. J Neurosci. 2008;28(38):9451-9462.
11. Yepes M, Brown SA, Moore EG, Smith EP, Lawrence DA, Winkles JA. A soluble fn14-fc decoy receptor reduces infarct volume in a murine model of cerebral ischemia. Am J Pathol. 2005;166(2):511-520.
12. Vendrame M, Gemma C, Pennypacker KR, et al. Cord blood rescues stroke-induced changes in splenocyte phenotype and func- tion. Exp Neurol. 2006;199(1):191-200.
13. Crowley MG, Liska MG, Borlongan CV.
Stem cell therapy for sequestering neuroin- flammation in traumatic brain injury: an update on exosome-targeting to the spleen. J Neurosurg Sci. 2017;61(3):291-302
14. Vahidy FS, Parsha KN, Rahbar MH, et al. Acute splenic responses in patients with ischemic stroke and intracerebral hemor- rhage. J Cereb Blood Flow Metab. 2016;36(6):1012-1021.
15. Swirski FK, Nahrendorf M, Etzrodt M, et al. Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science. 2009;325(5940):612-616.
16. Ajmo CT Jr, Vernon DO, Collier L, et al. The spleen contributes to stroke-induced neu- rodegeneration. J Neurosci Res. 2008;86(10): 2227-2234.
17. Chiba T, Umegaki K. Pivotal roles of mono- cytes/macrophages in stroke. Mediators Inflamm. 2013;2013:759103.
18. Offner H, Subramanian S, Parker SM, Afentoulis ME, Vandenbark AA, Hurn PD. Experimental stroke induces massive, rapid activation of the peripheral immune system. J Cereb Blood Flow Metab. 2006;26(5):654- 665.
19. 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(9):2616-2627.
20. Mashkouri S, Crowley MG, Liska MG, Corey S, Borlongan CV. Utilizing pharma- cotherapy and mesenchymal stem cell ther- apy to reduce inflammation following trau- matic brain injury. Neural Regen Res. 2016;11(9):1379-1384.
21. Tajiri N, Acosta SA, Shahaduzzaman M, et al. Intravenous transplants of human adi- pose-derived stem cell protect the brain from traumatic brain injury-induced neu- rodegeneration and motor and cognitive impairments: cell graft biodistribution and soluble factors in young and aged rats. J Neurosci. 2014;34(1):313-326.
22. Louveau A, Smirnov I, Keyes TJ, et al. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015;523(7560):337-341.
23. Ishikawa H, Tajiri N, Shinozuka K, et al. Vasculogenesis in experimental stroke after human cerebral endothelial cell transplanta-
tion. Stroke. 2013;44(12):3473-3481.
24. Yu SJ, Soncini M, Kaneko Y, Hess DC, Parolini O, Borlongan CV. Amnion: a potent graft source for cell therapy in stroke. Cell
Transplant. 2009;18(2):111-118.
25. Trakarnsanga K, Griffiths RE, Wilson MC, et
al. An immortalized adult human erythroid line facilitates sustainable and scalable gen- eration of functional red cells. Nat Commun. 2017;8:14750.
26. Tajiri N, Quach D, Kaneko Y, et al. Behavioral and histopathological assessment of adult ischemic rat brains after intracere- bral transplantation of NSI-566RSC cell lines. PLoS One. 2014;9(3):e91408.
27. Glover LE, Tajiri N, Lau T, Kaneko Y, van Loveren H, Borlongan CV. Immediate, but not delayed, microsurgical skull reconstruc- tion exacerbates brain damage in experi- mental traumatic brain injury model. PLoS One. 2012;7(3):e33646.
28. Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW. From inflamma- tion to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9(1):46-56.
29. Qureshi IA, Mehler MF. Towards a 'system- s'-level understanding of the nervous system and its disorders. Trends Neurosci. 2013;36(11):674-684.
30. Vendrame M, Cassady J, Newcomb J, et al. Infusion of human umbilical cord blood cells in a rat model of stroke dose-dependently rescues behavioral deficits and reduces infarct volume. Stroke. 2004;35(10):2390- 2395.
31. Schwarting S, Litwak S, Hao W, Bahr M, Weise J, Neumann H. Hematopoietic stem cells reduce postischemic inflammation and ameliorate ischemic brain injury. Stroke. 2008;39(10):2867-2875.
32. Barbosa da Fonseca LM, Gutfilen B, Rosado de Castro PH, et al. Migration and homing of bone-marrow mononuclear cells in chronic ischemic stroke after intra-arterial injection. Exp Neurol. 2010;221(1):122-128.
33. Yang B, Hamilton JA, Valenzuela KS, et al. Multipotent adult progenitor cells enhance recovery after stroke by modulating the immune response from the spleen. Stem Cells. 2017;35(5):1290-1302.
34. Koh HS, Chang CY, Jeon SB, et al. The hif-
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