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KR-102963004-B1 - Scaffold loaded with adipose-derived stem cells overexpressing PGC-1α for preventing or treating of liver fibrosis

KR102963004B1KR 102963004 B1KR102963004 B1KR 102963004B1KR-102963004-B1

Abstract

The present invention relates to a scaffold for the prevention or treatment of liver fibrosis, and more specifically, to a scaffold for the prevention or treatment of liver fibrosis loaded with adipose-derived stem cells overexpressing PGC-1α, prepared by transforming adipose-derived stem cells with a vector containing a gene encoding PGC-1α. Since the scaffold according to the present invention exhibits excellent therapeutic effects on liver fibrosis by inducing a decrease in blood concentration of alanine transaminases (ALT), a decrease in the expression of liver fibrosis markers, an increase in the expression of cell proliferation markers, and an increase in the expression of anti-apoptotic markers, it can be developed as an active ingredient in a composition for the prevention, treatment, or improvement of liver fibrosis.

Inventors

  • 김세준
  • 김옥희

Assignees

  • 가톨릭대학교 산학협력단

Dates

Publication Date
20260511
Application Date
20211223

Claims (15)

  1. A scaffold for the prevention or treatment of liver fibrosis loaded with stem cells transformed by a vector containing a gene encoding PGC-1α (peroxisome proliferator-activated receptor gamma coactivator-1 alpha), The above scaffold is composed of serum-derived components, and The above scaffold is a scaffold for the prevention or treatment of liver fibrosis, characterized in that it is for epidermal grafting.
  2. In paragraph 1, A scaffold for preventing or treating liver fibrosis, characterized in that the above-mentioned stem cells are adipose-derived stem cells (ASC).
  3. delete
  4. In paragraph 1, A scaffold for the prevention or treatment of liver fibrosis, characterized in that the liver fibrosis is induced by liver toxins.
  5. In paragraph 4, A scaffold for preventing or treating liver fibrosis, characterized in that the above-mentioned liver toxin is a substance that causes damage or disease to liver tissue and is one or more selected from the group consisting of thioacetamide (TAA), carbon tetrachloride (CCl4), tBHP (tert-butyl hydroperoxide), acetaminophen, tacrine, rubratoxin B, and hydrogen peroxide ( H₂O₂ ).
  6. A pharmaceutical composition for the prevention or treatment of liver fibrosis comprising, as an active ingredient, a scaffold loaded with stem cells transformed with a vector containing a gene encoding PGC-1α, The above scaffold is composed of serum-derived components, and A pharmaceutical composition for the prevention or treatment of liver fibrosis, characterized in that the scaffold above is for epidermal grafting.
  7. In paragraph 6, A pharmaceutical composition for preventing or treating liver fibrosis, characterized in that the above-mentioned stem cells are adipose-derived stem cells (ASC).
  8. delete
  9. In paragraph 6, A pharmaceutical composition for the prevention or treatment of liver fibrosis, characterized in that the liver fibrosis is induced by liver toxins.
  10. In Paragraph 9, A pharmaceutical composition for preventing or treating liver fibrosis, characterized in that the above-mentioned liver toxin is a substance that causes damage or disease to liver tissue and is one or more selected from the group consisting of thioacetamide (TAA), carbon tetrachloride (CCl4), tBHP (tert-butyl hydroperoxide), acetaminophen, tacrine, rubratoxin B, and hydrogen peroxide ( H₂O₂ ).
  11. A step of transforming isolated stem cells into a vector containing a gene encoding PGC-1α; and A step of loading the above-mentioned transformed stem cells onto a scaffold; A method for manufacturing a scaffold for the prevention or treatment of liver fibrosis comprising, The above scaffold is composed of serum-derived components, and A method for manufacturing a scaffold for the prevention or treatment of liver fibrosis, characterized in that the above scaffold is for epidermal grafting.
  12. In Paragraph 11, A method for manufacturing a scaffold for preventing or treating liver fibrosis, characterized in that the above-mentioned stem cells are adipose-derived stem cells (ASC).
  13. delete
  14. In Paragraph 11, A method for manufacturing a scaffold for the prevention or treatment of liver fibrosis, characterized in that the liver fibrosis is induced by liver toxins.
  15. In Paragraph 14, A method for manufacturing a scaffold for preventing or treating liver fibrosis, characterized in that the above-mentioned liver toxin is a substance that causes damage or disease to liver tissue and is one or more selected from the group consisting of thioacetamide (TAA), carbon tetrachloride (CCl4), tBHP (tert-butyl hydroperoxide), acetaminophen, tacrine, rubratoxin B, and hydrogen peroxide ( H₂O₂ ).

Description

Scaffold loaded with adipose-derived stem cells overexpressing PGC-1α for preventing or treating liver fibrosis The present invention relates to a scaffold for the prevention or treatment of liver fibrosis, and more specifically, to a scaffold for the prevention or treatment of liver fibrosis loaded with adipose-derived stem cells that overexpress PGC-1α, prepared by transforming adipose-derived stem cells with a vector containing a gene encoding PGC-1α. Liver fibrosis refers to a phenomenon in which hepatic stellate cells (HSCs) are activated due to repeated chronic liver disease, resulting in damage to liver tissue and infiltration of inflammatory cells, and the HSCs secrete collagen, the main substance of fibrosis, thereby forming thick fibrous septa in the liver. Generally, unlike liver cirrhosis, liver fibrosis is reversible, consists of thin fibrils, and does not form nodules. Furthermore, if the cause of liver damage is eliminated, recovery to normal may be possible. However, if this mechanism of liver fibrosis persists repeatedly, it progresses to irreversible liver cirrhosis characterized by increased crosslinking between connective tissues leading to the accumulation of thick fibrils and the loss of the normal structure of liver lobules to form nodules. Moreover, if liver cirrhosis persists, it eventually leads to liver cancer. Although stem cell research has demonstrated the potential for tissue regeneration and has made significant progress to date, clinical application remains very slow due to the absence of an "efficient delivery system for supplying large quantities of stem cells." Furthermore, despite the numerous potential benefits of stem cells, they have several drawbacks regarding clinical application. One of these is their short lifespan, with most stem cells disappearing within just a few days after transplantation. Additionally, stem cells can potentially transform into malignant tumors. Meanwhile, numerous studies have suggested that since the primary mechanism of action of stem cells is secretome-mediated, the secretomes secreted by stem cells may possess therapeutic potential similar to that of the stem cells themselves. The inventors sought a method to efficiently deliver a large quantity of stem cells to the human body via a scaffold, and in particular, investigated a method to simultaneously enhance both "efficacy" and "safety" in the treatment of liver fibrosis using stem cells. Accordingly, as a method to enhance the "efficacy" of stem cells, the inventors enhanced the therapeutic ability of stem cells by transgenerating them with PGC-1α (peroxisome proliferator-activated receptor gamma coactivator-1 alpha), a co-activator that promotes the transcriptional activity of various transcription regulators involved in mitochondrial biosynthesis and respiration. Furthermore, as a method to enhance the "safety" of stem cell therapy, the inventors introduced a scaffold loaded with stem cells; this enhances safety by trapping the stem cells within the scaffold, and since secretomes secreted by the stem cells can freely move outside the scaffold, a safer therapeutic effect can be expected. In the present invention, PGC-1α (peroxisome proliferator-activated receptor gamma coactivator-1 alpha) was introduced into adipose-derived stem cells to transform them into adipose-derived stem cells that overexpress PGC-1α, and then loaded onto a scaffold very similar to the extracellular matrix (ECM) of liver tissue to study the therapeutic effect on liver fibrosis in a mouse model of liver fibrosis. As a result, it was confirmed that they possess excellent anti-fibrotic ability, thereby completing the present invention. Figure 1 shows images of the condition of mouse liver tissue obtained at week 3 after implanting a scaffold loaded with PGC-1α-transformed adipose-derived stem cells into a liver fibrosis mouse model induced by thioacetamide (TAA) treatment. (“TAA+ASC” refers to the group in which PGC-1α-transformed adipose-derived stem cells were injected into the tail vein of the liver fibrosis model mouse, and “TAA+Scaffold-Mounted ASC” refers to the group in which a scaffold loaded with PGC-1α-transformed adipose-derived stem cells was implanted into the epidermis of the liver fibrosis model mouse.) Figure 2 shows the blood concentrations of alanine transaminases (ALT) (U/L) confirmed by serum tests at weeks 1, 2, and 3 after implanting a scaffold loaded with PGC-1α-transformed adipose-derived stem cells into a liver fibrosis mouse model induced by TAA treatment. (“TAA+ASC” refers to the group in which PGC-1α-transformed adipose-derived stem cells were injected into the tail vein of the liver fibrosis model mouse, and “TAA+Scaffold-Mounted ASC” refers to the group in which a scaffold loaded with PGC-1α-transformed adipose-derived stem cells was implanted into the epidermis of the liver fibrosis model mouse.) Figure 3 shows the results of H&E staining and analysis of mouse liver tissue obtained a