Mesenchymal stromal cells (MSCs) hold great promise in the treatment of diabetic retinopathy (DR), as evidenced by increasing preclinical and clinical studies. However, the absence of standardized and industrialized clinical-grade donor cells hampers the continued development and large-scale clinical application of MSCs-based therapies for DR. Previously, we have identified a unique population of MSCs generated from a clinical-grade human embryonic stem cell (hESC) line under Good Manufacturing Practice conditions that could be a potential source to address the issues. Here, we investigated the therapeutic potential of the clinical-grade hESC line–derived MSCs (hESC-MSCs) on db/db mice with DR. hESC-MSCs were initially characterized by morphological assessment, flow cytometry analysis and trilineage differentiation assays. These cells (5 × 10 cells) were then transplanted intravenously into 12-week-old db/db mice via tail vein, with phosphate-buffered saline transplantation and untreated groups used as controls. The retinal alterations in neural functions and microvascular perfusions, and inflammatory responses in peripheral blood and retina were evaluated at 4 and 6 weeks after transplantation using electroretinography, optical coherence tomography angiography and flow cytometry, respectively. Body weight and fasting blood glucose (FBG) levels were also measured to investigate their systemic implications. Compared with controls, intravenous transplantation of hESC-MSCs could significantly: (i) enhance impaired retinal electroretinography functions (including amplitudes of a-, b-wave and oscillatory potentials) at 4 weeks after transplantation; (ii) alleviate microvascular dysfunctions, especially in the inner retina with significance (including reducing non-perfusion area and increasing vascular area density) at 4 weeks after transplantation; (iii) decrease FBG levels at 4 weeks after transplantation and induce weight loss up to 6 weeks after transplantation and (iv) increase both peripheral blood and retinal interleukin-10 levels at 4 weeks after transplantation and modulate peripheral blood inflammatory cytokines and chemokines levels, such as monocyte chemotactic protein-1, up to 6 weeks after transplantation. The findings of our study indicated that intravenous transplantation of hESC-MSCs ameliorated retinal neural and microvascular dysfunctions, regulated body weight and FBG and modulated peripheral blood and retinal inflammation responses in a mouse model of DR. These results suggest that hESC-MSCs could be a potentially effective clinical-grade cell source for the treatment of DR.

中文翻译：

---

临床级人胚胎干细胞衍生的间充质基质细胞可改善 db/db 小鼠的糖尿病视网膜病变


越来越多的临床前和临床研究证明，间充质基质细胞 (MSC) 在治疗糖尿病视网膜病变 (DR) 方面具有巨大前景。然而，缺乏标准化和工业化的临床级供体细胞阻碍了基于间充质干细胞的DR疗法的持续开发和大规模临床应用。此前，我们已经确定了在良好生产规范条件下从临床级人胚胎干细胞 (hESC) 系产生的独特 MSC 群体，这可能是解决这些问题的潜在来源。在这里，我们研究了临床级 hESC 系衍生的 MSC (hESC-MSC) 对患有 DR 的 db/db 小鼠的治疗潜力。 hESC-MSC 最初通过形态学评估、流式细胞术分析和三系分化测定进行表征。然后将这些细胞（5×10个细胞）通过尾静脉静脉移植到12周龄的db/db小鼠中，磷酸盐缓冲盐水移植组和未处理组作为对照。移植后4周和6周分别使用视网膜电图、光学相干断层扫描血管造影和流式细胞术评估视网膜神经功能和微血管灌注的改变以及外周血和视网膜的炎症反应。还测量了体重和空腹血糖（FBG）水平以研究其系统影响。 与对照组相比，静脉移植 hESC-MSC 可以显着：（i）移植后 4 周增强受损的视网膜视网膜电图功能（包括 a 波、b 波幅度和振荡电位）； (ii) 移植后4周显着缓解微血管功能障碍，尤其是视网膜内层（包括减少非灌注区域和增加血管区域密度）； (iii)在移植后4周降低FBG水平并在移植后长达6周诱导体重减轻，以及(iv)在移植后4周增加外周血和视网膜白细胞介素10水平并调节外周血炎症细胞因子和趋化因子水平，例如单核细胞趋化蛋白-1，移植后长达 6 周。我们的研究结果表明，hESC-MSC 静脉移植可改善 DR 小鼠模型的视网膜神经和微血管功能障碍，调节体重和 FBG，并调节外周血和视网膜炎症反应。这些结果表明 hESC-MSC 可能是治疗 DR 的潜在有效的临床级细胞来源。