Mesenchymal Stem Cell Secretome Enhancement by Nicotinamide and Vasoactive Intestinal Peptide: A New Therapeutic Approach for Retinal Degenerative Diseases

Abstract

Mesenchymal stem cells (MSC) secrete neuroprotective molecules that may be useful as an alternative to cell transplantation itself. Our purpose was to develop different pharmaceutical compositions based on conditioned medium (CM) of adipose MSC (aMSC) stimulated by and/or combined with nicotinamide (NIC), vasoactive intestinal peptide (VIP), or both factors; and to evaluate in vitro their proliferative and neuroprotective potential. Nine pharmaceutical compositions were developed from 3 experimental approaches: (1) unstimulated aMSC-CM collected and combined with NIC, VIP, or both factors (NIC+VIP), referred to as the aMSC-CM combined composition; (2) aMSC-CM collected just after stimulation with the mentioned factors and containing them, referred to as the aMSC-CM stimulated-combined composition; and (3) aMSC-CM previously stimulated with the factors, referred to as the aMSC stimulated composition. The potential of the pharmaceutical compositions to increase cell proliferation under oxidative stress and neuroprotection were evaluated in vitro by using a subacute oxidative stress model of retinal pigment epithelium cells (line ARPE-19) and spontaneous degenerative neuroretina model. Results showed that oxidatively stressed ARPE-19 cells exposed to aMSC-CM stimulated and stimulated-combined with NIC or NIC+VIP tended to have better recovery from the oxidative stress status. Neuroretinal explants cultured with aMSC-CM stimulated-combined with NIC+VIP had better preservation of the neuroretinal morphology, mainly photoreceptors, and a lower degree of glial cell activation. In conclusion, aMSC-CM stimulated-combined with NIC+VIP contributed to improving the proliferative and neuroprotective properties of the aMSC secretome. Further studies are necessary to evaluate higher concentrations of the drugs and to characterize specifically the aMSC-secreted factors related to neuroprotection. However, this study supports the possibility of improving the potential of new effective pharmaceutical compositions based on the secretome of MSC plus exogenous factors or drugs without the need to inject cells into the eye, which can be very useful in retinal pathologies.

[Retracted] Vasoactive Drug Therapy and Clinical Nursing of Patients with Cardiovascular Disease

“…Especially in recent years, under the influence of factors such as population aging, dietary structure, and pollution, the incidence rate has increased. CVD has great harm to human health, and unhealthy behaviors can easily lead to the occurrence of cardiovascular diseases, as shown in Figure 3 [13,14]. According to the "2014 China Cardiovascular Disease Report," CVD has become the leading cause of disease-related death among urban and rural residents in China, with 44.8% in rural areas and 41.9% in urban areas.…”

Extracellular Vesicles from Human Adipose-Derived Mesenchymal Stem Cells: A Review of Common Cargos

“…Their therapeutic potential is being tested for the treatment of diverse diseases in musculoskeletal [12,52,57,[65][66][67][75][76][77][78] and cardiovascular systems [60,72,[79][80][81], nephrology [82,83], skin [62,68,[84][85][86] and immunology [71,87], among others. Surprisingly, we could only find one published study about the potential of human AT-MSC-EVs for the treatment of eye diseases [88], despite the fact that human AT-MSC and their conditioned media are being used in ophthalmology [89][90][91][92][93][94][95][96][97][98][99]. For instance, they are being used in 6 out of 403 registered clinical trials with these cells (ClinicalTrials.gov, N C T 0 4 4 8 4 4 0 2 N C T 0 3 8 7 8 6 2 8 , N C T 0 2 9 3 2 8 5 2 , NCT01808378, NCT02144103 and NCT02024269).…”

“…Surprisingly, we could only find one published study about the potential of human AT-MSC-EVs for the treatment of eye diseases [ 88 ], despite the fact that human AT-MSC and their conditioned media are being used in ophthalmology [ 89 – 99 ]. For instance, they are being used in 6 out of 403 registered clinical trials with these cells ( ClinicalTrials.gov , NCT04484402 NCT03878628, NCT02932852, NCT01808378, NCT02144103 and NCT02024269).…”

Retinal Neuroprotective Effect of Mesenchymal Stem Cells Secretome Through Modulation of Oxidative Stress, Autophagy, and Programmed Cell Death

“…These findings support the hypothesis that developing a cell-free therapeutic strategy based on the production of MSC secretome cocktails with neuroprotective characteristics may be an approach to treat RND. 11 – 14 The results reported here and in our previous studies 11 , 12 , 60 showed that the neuroprotective capacity of bmMSC secretome is higher than that of the secretome from adipose MSCs. In addition, an environment of retinal neurodegeneration, as shown in NR organ cultures, seems crucial for obtaining human bmMSC secretome with neuroprotective properties.…”