Lnk Gene-Modified Hematopoietic Cells for Sustained Blood Chimerism
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Solution Overview
Problem
Current methods fail to produce non-human animals that retain human blood cells at a high percentage for an extended period, particularly when using medium to large domestic animals as recipients, due to low survival rates of hematopoietic stem cells after birth.
Innovation Solution
Transplanting murine hematopoietic stem cells with a deleted Sh2b3/Lnk gene into pig fetuses, which enhances the survival and retention of human blood cells, achieving a blood chimerism of 10% or more for up to 16 months by modifying the function of genes acting on the hematopoietic system.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If human hematopoietic stem cells are transplanted into non-human animal fetuses using conventional methods, then blood chimerism can be achieved, but the survival rate of hematopoietic stem cells is low and blood chimerism level remains at several percent or less
Solution Approach 1:
The invention modifies the Lnk gene in donor hematopoietic stem cells to alter their biological parameters, specifically enhancing their ability to survive and proliferate in the recipient animal. This genetic parameter change transforms the cells' properties to overcome rejection and achieve high-level blood chimerism (10% or more) sustained for over 16 months.
Solution Approach 2:
The Lnk gene modification acts as an intermediary mechanism that mediates the interaction between donor and recipient immune systems. By disrupting the Lnk gene in donor cells, the invention creates a state where donor hematopoietic stem cells can evade host immune rejection without requiring severe immunosuppression of the recipient.
2Duration of action of stationary object
If conventional transplantation methods are used, then some blood chimerism can be achieved, but the chimeric state cannot be sustained for a long period of time after birth
Solution Approach 1:
The invention performs preliminary genetic modification of the Lnk gene in donor hematopoietic stem cells before transplantation. This advance preparation ensures that the cells are pre-equipped with enhanced survival capabilities, allowing them to maintain high-level blood chimerism for over 16 months after birth without declining, thereby sustaining the chimeric state long-term.
3Reliability
If HOXB4 gene overexpression is used to enhance hematopoiesis, then some improvement in cell survival is achieved, but the survival rate remains less than 10% and long-term chimerism is not sustained
Solution Approach 1:
The invention extracts or removes the Lnk gene function from donor hematopoietic stem cells through disruption. This extraction approach eliminates the inhibitory role of Lnk on hematopoietic stem cell proliferation and survival, achieving superior results compared to adding HOXB4 gene overexpression. The survival rate reaches 10% or more with sustained blood chimerism, overcoming the limitations of HOXB4-based methods.
Data Source
AI summary
The present invention discloses a novel means capable of producing a blood chimeric animal in which a state of retaining blood cells originating in a heterologous animal at a high percentage is sustained for a long period of time. The method for producing a non-human animal that retains blood cells originating in a heterologous animal, according to the present invention, comprises transplanting hematopoietic cells of a heterologous animal into a non-human animal, in which hematopoietic cells the function of a gene that acts on the hematopoietic system is modified, The gene that acts on the hematopoietic system is, for example, Lnk gene, When a medium to large mammal is used as a recipient, the survival rate of hematopoietic cells originating in a heterologous animal is dramatically increased such that blood chimerism of 10% or more can be maintained even in a 16 month old animal.