SLFN11-Modified Mesenchymal Stem Cells for Delayed Senescence
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Solution Overview
Problem
The challenge of mesenchymal stem cell (MSC) senescence during in vitro expansion leads to loss of functional characteristics and potential risks in clinical applications, including immune rejection and canceration, due to replicative senescence and DNA damage, which current methods have not adequately addressed.
Innovation Solution
Overexpression of the Schlafen (SLFN) family gene member 11 (SLFN11) in human mesenchymal stem cells using lentiviral transfection to delay senescence and maintain pluripotency, achieved by constructing an immortalized hMSC cell line and comparing gene expression profiles.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If in vitro expansion is performed to obtain sufficient cell numbers for clinical treatment, then the cell quantity increases, but cell senescence occurs leading to loss of function and heterogeneity
Solution Approach 1:
The patent changes the biological parameter of gene expression by overexpressing SLFN11 in MSCs. This genetic modification alters the cellular state to resist senescence, enabling cells to maintain functional stability while undergoing extensive in vitro expansion to achieve clinical dosing requirements
2Duration of action of moving object
If long-term in vitro expansion is performed, then sufficient cell biomass is obtained, but DNA damage accumulates leading to replicative senescence
Solution Approach 1:
The patent applies preliminary anti-action by pre-modifying MSCs with overexpressed SLFN11 before expansion. This genetic enhancement provides preemptive protection against DNA damage accumulation, allowing the cells to undergo long-term expansion without acquiring senescence-associated DNA lesions
3Quantity of substance
If senescent MSCs are used for therapy, then cell numbers are sufficient, but therapeutic risks increase including immune rejection and canceration
Solution Approach 1:
The patent extracts and eliminates the senescence problem by genetically modifying MSCs to overexpress SLFN11. This modification removes the senescence barrier, enabling production of sufficient cell doses without the harmful effects of senescence such as immune rejection and tumorigenicity risks
Data Source
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AI summary
The invention discloses a method for delaying senescence of human mesenchymal stem cells. The method delays the senescence of human mesenchymal stem cells through the overexpression of an SLFN11 gene in human mesenchymal stem cells. A human mesenchymal stem cell senescence model includes a replicative hMSC senescence model and a DNA damage-induced hMSC senescence model. The overexpression of the SLFN11 gene is achieved by infecting human mesenchymal stem cells with lentivirus. In addition, the invention further provides an application of a modified human mesenchymal stem cell in the preparation of a drug for treating ulcerative colitis. The invention adopts the replicative hMSC senescence model and the DNA damage-induced hMSC senescence model, and uses lentiviral infection technology to make these two senescence cell models overexpress SLFN11, which can significantly reduce the aging phenotype of the replicative hMSC aging model and the hMSC aging model caused by camptothecin-induced DNA damage; when the cells are inoculated subcutaneously into a nude mouse, there is no chromosomal abnormalities or tumorigenicity, and when the cells are transplanted into a mouse model of ulcerative colitis, there is no immune exclusion reaction and has better therapeutic effects than the normal hMSCs.