Transplantation Site Affects the Outcomes of Adipose-Derived Stem Cell-Based Therapy for Retinal Degeneration
Transplantation Site Affects the Outcomes of Adipose-Derived Stem Cell-Based Therapy for Retinal Degeneration
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移植部位影响脂肪干细胞视网膜变性治疗的结果
DOI：
10.1155/2020/9625798
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发表时间：
2020-01-06
影响因子：
4.3
通讯作者：
Tian, Haibin
中科院分区：
文献类型：
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作者：
Hu, Chengyu;La, Huanzhi;Tian, Haibin
脂肪干细胞（Adipose-derived stem cells，ASCs）移植到视网膜下腔后对视网膜退行性疾病（retinal degenerative diseases，RDD）有很强的保护作用。最近，已经进行了几项临床试验来用玻璃体内移植干细胞（包括ASC）来治疗RDD。然而，临床试验的结果并不令人满意。为了研究移植部位是否会改变干细胞治疗RDD的结果，我们分离了大鼠ASCs（rASCs）并用绿色荧光蛋白标记它们。将自体rASCs移植到由碘酸钠（SI）诱导的大鼠RDD模型的玻璃体腔或视网膜下腔中。用ERG记录电反应。于移植后1、2、4周取大鼠眼冰冻切片，观察视网膜的解剖结构。免疫组化法观察神经视网膜细胞凋亡和视网膜前膜样结构的形成。玻璃体内移植rASCs后，神经视网膜的电反应消失，但玫瑰花结形成和凋亡减少。然而，移植到视网膜下腔的rASCs保护视网膜免受SI引起的损伤，包括部分恢复电反应和减少玫瑰花结形成。玻璃体内移植的rASC形成膜，导致注射部位的视网膜折叠。Müller细胞、视网膜色素上皮细胞和小胶质细胞从视网膜迁移到rASC形成的膜，随后形成ERM样结构。此外，玻璃体液促进rASC迁移，rASC条件培养基增强Müller细胞迁移，如体外研究所示。这些数据表明，玻璃体腔不是基于ASC的RDD治疗的良好移植部位，并且在临床试验中，在将干细胞移植到玻璃体腔中以治疗RDD之前应做出慎重的决定。
Adipose-derived stem cells (ASCs) have shown a strong protective effect on retinal degenerative diseases (RDD) after being transplanted into the subretinal space in an animal model. Recently, several clinical trials have been conducted to treat RDD with intravitreal transplantation of stem cells, including ASCs. However, the outcomes of the clinical trials were not satisfactory. To investigate if the transplantation site alters the outcome of stem cell-based therapy for RDD, we isolated rat ASCs (rASCs) and labeled them with green fluorescent protein. Autologous rASCs were grafted into the vitreous chamber or subretinal space in a rat RDD model induced by sodium iodate (SI). The electric response was recorded by ERG. The anatomic structure of the retina was observed in cryosections of rat eyes at posttransplantation weeks 1, 2, and 4. Neural retina apoptosis and epiretinal membrane- (ERM-) like structure formation were investigated by immunostaining. The intravitreal transplantation of rASCs resulted in an extinguished electric response, although the rosette formation and apoptosis of neural retina were reduced. However, the rASCs that grafted in the subretinal space protected the retina from the damage caused by SI, including a partial recovering of the electric response and a reduction in rosette formation. Intravitreally grafted rASCs formed a membrane, resulting in retina folding at the injection site. Müller cells, retinal pigment epithelial cells, and microglial cells migrated from the retina to the rASC-formed membrane and subsequently formed an ERM-like structure. Furthermore, vitreous fluid promoted rASC migration, and rASC-conditioned medium enhanced Müller cell migration as indicated by in vitro studies. These data suggested that the vitreous chamber is not a good transplantation site for ASC-based therapy for RDD and that a deliberate decision should be made before transplantation of stem cells into the vitreous chamber to treat RDD in clinical trials.