睾丸中注射PIN1恢复精子干细胞

2021/3/19 11:26:03 本站原创 佚名 【字体:

编译   廖联明

 

男性不育通常是因为精液中缺少精子,这可能是由于血睾丸屏障(BTB)受损造成的。这种屏障保护生殖细胞免受有害毒物和药物的侵害,一种叫做PIN1的蛋白质对其功能很重要。缺乏PIN1的老鼠是不育的,睾丸小,精子干细胞枯竭,精子数量少。尽管科学家们已经考虑过基因疗法来治疗男性不育,但这些方法是有风险的,因为它们可能会导致生殖细胞中不必要的基因改变,并可能遗传给后代。Hyun Mo Ryoo和他的同事们想开发一种系统,将蛋白质(如PIN1)而不是基因输送到睾丸,但首先他们必须找到一种方法,使蛋白质通过睾丸的复杂管道进入细胞。

研究人员开发了一种称为纤维复合物(Fibroplex)的传递系统,它由丝素蛋白制成的球形纳米颗粒和一层脂质涂层组成。他们将PIN1装载到Fibroplex中,结果表明这些纳米粒是安全的,并且在小鼠身上没有毒性或睾丸损伤的迹象。当研究小组将PIN1负载的纤维复合物注射到PIN1缺失的年轻小鼠的睾丸中时,治疗恢复了几乎正常的PIN1水平和精子干细胞数量,并修复了BTB。实验组小鼠睾丸重量和大小正常,精子数量约为野生型小鼠的50%。直到治疗后大约5个月,当蛋白质降解时,PIN1纤维蛋白复合物治疗的小鼠的幼崽数量与野生型小鼠相似,而PIN1缺失的未经治疗的小鼠仍然不能生育。研究人员说,这是第一次证明蛋白质直接进入睾丸治疗男性不育。

 

——原文

Delivering PIN1 to testes could restore sperm stem cells

 

Male infertility often happens because of a lack of sperm in the semen, which can result from damage to the blood-testis barrier (BTB). This barrier protects reproductive cells from harmful

toxicants and drugs, and a protein called PIN1 is important for its function. Mice genetically engineered to lack PIN1 are infertile, with small testes, depleted sperm stem cells and a low sperm count. Although scientists have considered gene therapies to treat male infertility, these procedures are risky because they could cause unwanted genetic changes in reproductive cells that might be passed onto offspring. Hyun-Mo Ryoo and colleagues wanted to develop a system to deliver proteins (such as PIN1) instead of genes to the testes, but first they had to find a way to get proteins through the complex tubes of the testicles and into cells.

 

The researchers developed a delivery system called Fibroplex, which consisted of spherical nanoparticles made of silk fibroin and a coating of lipids. They loaded PIN1 into Fibroplex, and showed that the particles appeared safe and didn't show signs of toxicity or testicular damage in mice. When the team injected the PIN1-loaded Fibroplex into the testes of young mice with PIN1 deletions, the treatment restored nearly normal PIN1 levels and sperm stem cell numbers and repaired the BTB. Treated mice had normal testicular weight and size and about 50% of the sperm count of wild-type mice. Until about 5 months after treatment, when the protein degraded, the PIN1-Fibroplex-treated mice fathered a similar number of pups as wild-type mice, whereas untreated mice with PIN1 deletions remained infertile. This is the first demonstration of direct delivery of proteins into the testis to treat male infertility, the researchers say.

 

Journal Reference:

 

    Woo Jin Kim, Bong Soo Kim, Hyun Jung Kim, Young Dan Cho, Hye Lim Shin, Hee In Yoon, Yun Sil Lee, Jeong-Hwa Baek, Kyung Mi Woo, Hyun-Mo Ryoo. Intratesticular Peptidyl Prolyl Isomerase 1 Protein Delivery Using Cationic Lipid-Coated Fibroin Nanoparticle Complexes Rescues Male Infertility in Mice. ACS Nano, 2020; DOI: 10.1021/acsnano.0c04936

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