Page 225 - 2019_05-HaematologicaMondo-web

Brain to spleen stem cell migration
cal and translational advantages of using human cells in an immunocompetent rat model, we recognize the possibili- ty that the present results may be due to the phenomenal cross-species immunomodulation platform created by this model. We also concede that a same-species transplant paradigm may need to confirm the present observation of inflammation- and lymphatic-mediated brain-to-spleen migration of grafted stem cells. Notwithstanding this lim- itation, we submit that the current xeno-transplantation paradigm exaggerates the role of inflammation and/or the immune system on the lymphatic systems and stem cell fate, i.e., migration. As inhibiting lymphatic vessel con- traction is associated with immunosuppression, it is pos- sible that suppressing the immune system in an immuno- suppressed rat model would hinder the lymphatic sys- tem’s ability to coordinate lymph flow and thus obstruct the migration of hBMSC from the brain to the spleen.53
Despite being a subject of debate, the optimal time point for the application of stem cells in the clinical set- ting exists, both in terms of stem cell tropism toward the brain and overall therapeutic effectiveness. The undecid- ed nature of this ideal time point is, however, a major hurdle to progress in stem cell therapies in stroke. In our study, rats were reperfused 1 hour after the middle cere- bral artery occlusion surgery and received hBMSC at this point. Preclinical studies reveal that at this acute phase of stroke, the levels of chemokines and trophic factors increase markedly in the infarcted brain and subsequent- ly decrease over time.54 This large release of inflammato- ry factors, oxygen free radicals, and excitatory neuro- transmission toxins (e.g., glutamate and glycine) may pose a threat to the survival of the recently transplanted stem cells. The application of stem cells during the acute phase of stroke may be necessary to offer a range of
paracrine and immunomodulatory effects significant enough to reduce secondary injury processes and stimu- late brain repair after stroke.55 Admittedly, 1 hour after a stroke is not the most clinically feasible time. However, later deliveries are plagued by the existence of a non- conducive microenvironment after cerebral infarction which may interfere with the transplanted stem cells’ ability to survive. Thus, it is important to determine the ideal, realistic time point, when the transplanted cells can not only survive in the infarcted area and salvage affect- ed brain tissue, but also, as this study shows, effectively modulate peripheral immune responses to reduce the harmful inflammation. This requires more in-depth research. Here, we demonstrated a phenomenon where- by intracerebrally transplanted stem cells can migrate to the spleen via the lymphatic system, propelled by inflammatory signals. However, characterizing the func- tion of the stem cells once within the spleen, how this in turn affects global inflammatory factors, and the ultimate effects on brain health, are mechanisms which require deeper study.
This study supports an alternative mechanism essential to cell therapy for stroke, advancing the notion that while the brain is the ultimate therapeutic target of stem cells, achieving functional recovery may occur as a systematic event. The intuitive mechanism whereby stem cells replace dead and dying neurons, integrating into function- al circuits, only occurs to a slight extent.56 Thus, a com- plete explanation for the functional recovery associated with stem cell therapies in stroke requires an understand- ing of the non-cell replacement mechanisms of stem cells. Intracerebrally transplanted hBMSC phagocytose apop- totic neurons, depart from the ischemic tissue of the brain, and travel toward the spleen via lymphatic vessels. From
Figure 8. Illustration demonstrating how stem cells migrate from the brain to the spleen via lymphatic vessels and with guidance from inflammatory cells. Stem cells engrafted in the brain enter lymphatic vessels in the brain and inflammatory cues direct the transplanted stem cells toward the spleen.
haematologica | 2019; 104(5)
1071