Subpopulations of Bone Marrow Mesenchymal Stem Cells Exhibit Differential Effects in Delaying Retinal Degeneration

Abstract

Bone marrow mesenchymal stem cells (BMSCs) have a therapeutic role in retinal degeneration (RD). However, heterogeneity of BMSCs may be associated with differential therapeutic effects in RD. In order to confirm this hypothesis, two subsets of rat BMSCs, termed rBMSC1 and rBMSC2, were obtained, characterized and functionally evaluated in the treatment of RD of Royal College of Surgeons (RCS) rats. Both subpopulations expressed mesenchymal stem cells (MSC) markers CD29 and CD90, but were negative for hemacyte antigen CD11b and CD45 expression. In comparison with rBMSC2, rBMSC1 showed higher rate of proliferation, stronger colony formation, and increased adipogenic potential, whereas rBMSC2 exhibited higher osteogenic potential. Microarray analysis showed differential gene expression patterns between rBMSC1 and rBMSC2, including functions related to proliferation, differentiation, immunoregulation, stem cell maintenance and division, survival and antiapoptosis. After subretinal transplantation in RCS rats, rBMSC1 showed stronger rescue effect than rBMSC2, including increased b-wave amplitude, restored retinal nuclear layer thickness, and decreased number of apoptotic photoreceptors, whereas the rescue function of rBMSC2 was essentially not better than the control. Histological analysis also demonstrated that rBMSC1 possessed a higher survival rate than rBMSC2 in subretinal space. In addition, treatment of basic fibroblast growth factor, an accompanying event in subretinal injection, triggered more robust increase in secretion of growth factors by rBMSC1 as compared to rBMSC2. Taken together, these results have suggested that the different therapeutic functions of BMSC subpopulations are attributed to their distinct survival capabilities and paracrine functions. The underlying mechanisms responsible for the different functions of BMSC subpopulation may lead to a new strategy for the treatment of RD.

Transplantation Site Affects the Outcomes of Adipose-Derived Stem Cell-Based Therapy for Retinal Degeneration

“…Electroretinogram (ERG) Examination. After the cell transplantation, ERG b-wave amplitude was measured weekly up to 4 weeks posttransplantation, with AVES-2000 electrophysiological apparatus (Kanghuaruiming S&T, Chongqing, China) as described previously [13,14]. An intensity of 6.325e-2 cd * s/m was applied, which allowed the recording of the response of photoreceptors to light stimulation.…”

“…In addition to ASCs, other kinds of mesenchymal stem cell-based therapies for RDD have also shown promising outcomes in animal RDD models [13][14][15], prompting scientists and doctors to conduct clinical trials. The outcomes of several clinical trials have shown that some patients who received intravitreal transplantation of human ASCs have dense vitreous hemorrhage in the eyes, retinal detachment with severe proliferative vitreoretinopathy (PVR), and secondary epiretinal membrane (ERM) formation [16,17].…”

“…When stem cells are used to treat RDD, cells can be transplanted into the subretinal space or the vitreous chamber. Most published papers demonstrated that when stem cells, including ASCs, were grafted into the subretinal space, grafted cells stayed in the subretinal space and showed protective functions [12][13][14][15]. However, previous clinical trials have preferred the vitreous chamber as the transplantation site (http://www.clinicaltrials.gov, NCT02016508, NCT01518127, NCT03772938, NCT01920867, NCT03011541, NCT02024269, NCT0106856, NCT01560715, NCT01531348, and NCT02280135).…”

Adipose Tissue-Derived Mesenchymal Stem Cells Have a Heterogenic Cytokine Secretion Profile

“…There is heterogeneity in the differentiation potential of MSC [20, 21], and there is heterogeneity in the expression of cell surface markers such as STRO-1 and CD271, and STRO-1 and CD271 expressing MSC have been demonstrated to possess enhanced immunomodulatory capacity [22, 23]. The heterogeneity of MSC may impair their therapeutic efficacy and introduce variations between studies [24].…”

Progress of stem/progenitor cell-based therapy for retinal degeneration

“…Other typical examples included CX3CL1-expressing MSCs [115] and NT-4-engineered MSCs [116]. To date, most studies have supported the neuroprotective effect of MSCs [117], while rare evidence of neuronal replacement has been reported by means of MSC transplantation. According to observations by researchers, the mechanism of photoreceptor survival promotion is that MSCs strictly regulate their self-renewal capacity through anti-apoptotic, anti-inflammatory, immunomodulatory and angiogenic effects, which are based on MSC secretion of cytokines [118], growth factors and proteins, such as vascular endothelial growth factor, stromal cell-derived factor 1-alpha [119] and progranulin [12].…”