The Benefits and Hazards of Intravitreal Mesenchymal Stem Cell (MSC) Based-Therapies in the Experimental Ischemic Optic Neuropathy

Abstract

Mesenchymal stem cell (MSC) therapy has been investigated intensively for many years. However, there is a potential risk related to MSC applications in various cell niches. Methods: The safety of intravitreal MSC application and the efficacy of MSC-derived conditioned medium (MDCM) were evaluated in the normal eye and the diseased eye, respectively. For safety evaluation, the fundus morphology, visual function, retinal function, and histological changes of the retina were examined. For efficacy evaluation, the MDCM was intravitreally administrated in a rodent model of anterior ischemic optic neuropathy (rAION). The visual function, retinal ganglion cell (RGC) density, and neuroinflammation were evaluated at day 28 post-optic nerve (ON) infarct. Results: The fundus imaging showed that MSC transplantation induced retinal distortion and venous congestion. The visual function, retinal function, and RGC density were significantly decreased in MSC-treated eyes. MSC transplantation induced astrogliosis, microgliosis, and macrophage infiltration in the retina due to an increase in the HLA-DR-positive MSC proportion in vitreous. Treatment with the MDCM preserved the visual function and RGC density in rAION via inhibition of macrophage infiltration and RGC apoptosis. Conclusions: The vitreous induced the HLA-DR expression in the MSCs to cause retinal inflammation and retina injury. However, the MDCM provided the neuroprotective effects in rAION.

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

“…Xenotransplants are used in preclinical models to test therapeutic effects of human cells in animals prior translation into clinic. Works from our lab ( Millán-Rivero et al, 2018 ) and others ( Wen et al, 2021 ) show that even when human cells neuroprotect, they also trigger an immune response that alters the host anatomically and functionally, as we show here as well. Neuroprotection using human cells seems to be dependent on the type of MSCs and neurons: hWJ-MSCs (perinatal MSCs isolated from the umbilical cord Wharton’s jelly) rescue Brn3a + RGCs ( Millán-Rivero et al, 2018 ; Wen et al, 2021 ) while here we show that hBM-MSCs do not rescue them but do rescue the other functional subtype, m + RGCs.…”

“…MSCs are known for their immunomodulating properties, and secretion of paracrine factors ( Khan and Newsome, 2019 ) both properties may be part of the therapeutic effect observed here and in other works using as model the injured retina ( Zaverucha-do-Valle et al, 2011 ; Lucas-Ruiz et al, 2019a ; Mesentier-Louro et al, 2019 ; Wen et al, 2021 ) or spinal cord ( Ankeny et al, 2004 ; Wright et al, 2011 . Reviewed in; Staff et al, 2019 ).…”

Transplanted Mouse Embryonic Stem Cell–Derived Retinal Ganglion Cells Integrate and Form Synapses in a Retinal Ganglion Cell-Depleted Mouse Model

“… 48 , 49 Also, the transplantation itself could also cause an immune response due to allogeneic rejection. 50 In this study, NMDA treatment, transplantation, and transplantation with NMDA treatment similarly activated Müller cells and microglia, but there was no significant difference among these three conditions ( Supplementary Fig. S2 ).…”

Retinal Ganglion Cell Transplantation: Approaches for Overcoming Challenges to Functional Integration

“…Additionally, allogenic MSC transplantation has been documented to cause hazards to the recipient [194,195]. Perturbed visual function, retinal detachment [196], RGC loss, and venous congestion have been reported as a result of transplanted MSCs triggering intraocular inflammation [197], and they may be a concern for other cell types as well. Furthermore, stem cell derived RGCs may differ from native RGCs in unexpected ways.…”