Neuroprotection and Axonal Regeneration Induced by Bone Marrow Mesenchymal Stromal Cells Depend on the Type of Transplant

Abstract

Mesenchymal stromal cell (MSC) therapy to treat neurodegenerative diseases has not been as successful as expected in some preclinical studies. Because preclinical research is so diverse, it is difficult to know whether the therapeutic outcome is due to the cell type, the type of transplant or the model of disease. Our aim here was to analyze the effect of the type of transplant on neuroprotection and axonal regeneration, so we tested MSCs from the same niche in the same model of neurodegeneration in the three transplantation settings: xenogeneic, syngeneic and allogeneic. For this, bone marrow mesenchymal stromal cells (BM-MSCs) isolated from healthy human volunteers or C57/BL6 mice were injected into the vitreous body of C57/BL6 mice (xenograft and syngraft) or BALB/c mice (allograft) right after optic nerve axotomy. As controls, vehicle matched groups were done. Retinal anatomy and function were analyzed in vivo by optical coherence tomography and electroretinogram, respectively. Survival of vision forming (Brn3a+) and non-vision forming (melanopsin+) retinal ganglion cells (RGCs) was assessed at 3, 5 and 90 days after the lesion. Regenerative axons were visualized by cholera toxin β anterograde transport. Our data show that grafted BM-MSCs did not integrate in the retina but formed a mesh on top of the ganglion cell layer. The xenotransplant caused retinal edema, detachment and folding, and a significant decrease of functionality compared to the murine transplants. RGC survival and axonal regeneration were significantly higher in the syngrafted retinas than in the other two groups or vehicle controls. Melanopsin+RGCs, but not Brn3a+RGCs, were also neuroprotected by the xenograft. In conclusion, the type of transplant has an impact on the therapeutic effect of BM-MSCs affecting not only neuronal survival but also the host tissue response. Our data indicate that syngrafts may be more beneficial than allografts and, interestingly, that the type of neuron that is rescued also plays a significant role in the successfulness of the cell therapy.

Immune recognition of syngeneic, allogeneic and xenogeneic stromal cell transplants in healthy retinas

“…The neuroprotective role of IL-6 goes through modulation of excitability and function by regulating voltage-gated and receptor operated channels, which in turn are critical for neuronal electrical functionality (reviewed in [ 55 – 57 ]). Here, levels of IL-6 three times higher than basal conditions did not cause RGC death, and thus, it is tempting to speculate that in this context IL-6 is not detrimental but beneficial, which concords with the maintenance of functionality seen here and the neuroprotective and neuroregenerative properties of syngeneic BM-MSCs [ 18 ].…”

“…Previously, we showed that the syngeneic intravitreal transplant of BM-MSCs was neuroprotective and promoted axonal regeneration of axotomized RGCs, while allogeneic transplant did not differ from un-transplanted retinas. Xenogeneic transplant, however, impaired retinal functionality further than axotomy alone [ 18 ]. Those data tie beautifully with data presented here, where we show that in the healthy retina, the syngeneic transplants neither alter retinal function nor cause glial activation, while allo- and xenotransplants do, being the latter the most damaging transplant.…”

“…Many preclinical studies on MSC neuroprotective properties have shown promising results [ 14 , 18 , 26 , 27 ]. However, there is a lack of concordance between the extensive research on MSC neuroprotection and clinical translation as evidenced by the few clinical trials currently using this strategy (clinicaltrials.gov).…”

“…In addition, patients receiving allotransplants undergo immunosuppression to prevent graft rejection, a practice that is not always used in animal models, even when receiving human cells. The effect of the transplant is essential because the host immune response may radically change the therapeutic outcome [ 18 , 28 ], graft survival, tissue homeostasis and immune response to the graft.…”

Current Status of Mesenchymal Stem/Stromal Cells for Treatment of Neurological Diseases

“…These findings contrast with other reports that MSCs injected intravitreally did not integrate into the rat retina (Hill et al, 2009 ), and even after 18 weeks post-injection, the majority of BM-MSCs remained in the vitreous body (Mesentier-Louro et al, 2014 ). Importantly, a recent study indicated that care with the type of transplantation of cells (syngeneic, allogeneic, or xenogeneic) may impact the results, since MSCs from different donor species can exert different effects (Norte-Munoz et al, 2021 ).…”