Release date: 2017-08-08
Recently, a research team at the University of Chicago brought a study of “big brainsâ€, in which researchers validated a new form of gene therapy – treating patients with type 2 diabetes by transplanting genetically edited skin. And obesity, this skin graft-based gene therapy may be able to treat a variety of human diseases. The study was published in the August 3, 2017 issue of Cell Stem Cell.
What kind of spark will the gene editing + stem cell + skin transplant collide? Recently, a research team at the University of Chicago brought a study of “big brainsâ€, in which researchers validated a new form of gene therapy – treating patients with type 2 diabetes by transplanting genetically edited skin. And obesity, this skin graft-based gene therapy may be able to treat a variety of human diseases. The study was published in the August 3, 2017 issue of Cell Stem Cell.
Dr. Xiaoyang Wu, a senior author of the study and assistant professor at the University of Chicago, said: "We have overcome some technical barriers and designed a skin graft model from mouse to mouse in animals with intact immune systems. We think this The platform has the potential to promote safe and long-lasting gene therapy, and hopefully one day it will be able to screen and modify skin cells for gene therapy in humans."
Construction of mouse skin organs
As early as the 1970s, doctors knew how to get skin stem cells from large-area burn patients, culture them in the laboratory, and then use the growing tissue to repair the patient's wounds. This method has now become the standard. However, skin transplantation applications are not as developed in humans as humans.
“The mouse skin transplant system is not very mature,†Wu said. “We spent several years optimizing our 3D skin-like organ culture system.â€
The study, entitled Engineered Epidermal Progenitor Cells CanCorrect Diet-Induced Obesity and Diabetes, demonstrates for the first time that engineered skin grafts can survive long-term in wild-type mice with intact immune systems. “Our skin transplant success rate is higher than 80%,†Wu said. “This is very exciting for us.â€
Researchers choose diabetes because the pathology is not related to the skin, and secondly diabetes can be treated by delivering specific proteins.
Image source: Cell Stem Cell
Inserting an inducible GLP1 gene into skin cells
The researchers chose to insert the glucagon-like peptide 1 (GLP1) gene into skin cells, and glucagon-like peptide 1 (GLP1) stimulates the pancreas to secrete insulin. These extra insulins remove excess glucose from the blood and prevent diabetic complications. GLP1 also delays gastric emptying and reduces appetite.
The researchers then used CRISPR to edit the GLP1 gene. They inserted a mutation that extended the half-life of the hormone in the blood and fused the modified gene to the antibody fragment, allowing it to last longer in the blood circulation. The researchers also attached an inducible promoter to the gene, which enabled them to use the doxycycline to induce GLP1 gene expression. They then insert the gene into the skin cells and culture the cells.
Immunofluorescence imaging showed that the skin graft had normal skin differentiation and tissue structure. Image source: Cell Stem Cell
When these cultured cells are exposed to the air/liquid interface, the cells begin to stratify, producing a "skin-like organ." The researchers then transplanted the genetically engineered skin grown in the lab to mice with intact immune systems. There was no significant rejection of the skin graft.
The weight and blood glucose levels of mice expressing GLP1 gene were effectively controlled
Next, the researchers fed a control diet and genetically modified mice to a high-fat diet, and the mice in both groups gained weight rapidly. When the high-fat diet and doxycycline were fed to the control group and the genetic modification group, the control mice were significantly obese, while the insulin levels in the blood of mice expressing GLP1 were significantly increased, blood glucose levels were lowered, and body weight was effectively controlled.
Mice expressing the GLP1 gene (left) had less weight gain on the high-fat diet and the doxycycline diet than the control mice (right). Image source: Cell Stem Cell
"Our data surface, skin gene therapy that induces expression of GLP1 can be used to treat and prevent diet-induced obesity and pathology," the authors write. "When researchers transplant genetically engineered human cells into immunocompromised mice, They also saw the same effect. These results suggest that "GLP1 secreted skin gene therapy may have clinical utility."
Or can be applied to a variety of human diseases
The authors point out that this combination of in vitro precise genome editing and efficient application of engineered cells in vivo can provide "significant help in treating multiple human diseases."
Wu said: "We believe this can provide a long-term safe option for the treatment of a variety of diseases. It can be used to deliver therapeutic proteins, replace missing proteins, such as hemophilia, in patients with genetic defects. Or as a metabolic library, remove each Toxins."
Skin progenitor cells are ideal for gene therapy because of its unique advantages: human skin is the largest and most accessible organ in the body; it is easy to monitor; if necessary, the transplanted skin can be quickly removed. Skin cells proliferate rapidly in culture and are easy to transplant; skin grafting processes are relatively safe, minimally invasive and inexpensive.
Reference material
Gene therapy via skin could treat many diseases, even obesity
Engineered Epidermal Progenitor Cells Can Correct Diet-Induced Obesity and Diabetes
Source: Bio-Exploration (micro-signal biodiscover)
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