Transgenic Rodent Expressing Human IL-34 for Microglia Retention
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Solution Overview
Problem
Humanized mice currently available are unable to retain a large number of human microglia, making them insufficient for simulating HIV infection in the central nervous system effectively.
Innovation Solution
A transgenic rodent expressing human interleukin-34 (IL-34) is created by transplanting human CD34-positive hematopoietic stem cells, which induces the production and retention of human microglia, and subsequent HIV infection to simulate HIV infection in the CNS.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If human CD34-positive hematopoietic stem cells are transplanted into conventional immunodeficient mice, then human immune cells are reconstructed, but human microglia are not retained in the brain
Solution Approach 1:
Human IL-34 is introduced as an intermediary factor to mediate between the transplanted human CD34-positive hematopoietic stem cells and the mouse brain environment. This human cytokine acts as a signaling mediator that directs the differentiation of human stem cells into microglia and promotes their retention in the central nervous system, resolving the incompatibility between human cells and mouse brain environment.
Solution Approach 2:
The invention changes the biochemical parameter of the rodent system by introducing human IL-34, which alters the differentiation signals available to transplanted human stem cells. This parameter change enables the stem cells to differentiate along the microglial lineage rather than following default mouse microglia development pathways, thereby achieving human microglia retention.
2Adaptability or versatility
If human CD34-positive hematopoietic stem cells are transplanted into immunodeficient mice, then human immune system is reconstituted, but the model is insufficient for simulating HIV infection in the CNS
Solution Approach 1:
Human IL-34 serves as a critical intermediary that creates a human-compatible microenvironment in the mouse brain. This mediator enables the establishment of human microglia, which are the actual target cells for HIV-1 infection in the CNS, thereby making the model adaptable for studying HIV pathogenesis in the central nervous system.
3Quantity of substance
If conventional humanized mouse models are used, then human immune cells are present, but microglia distribution and number are insufficient
Solution Approach 1:
The introduction of human IL-34 as a transgenic element or administered factor provides a simple yet effective mechanism to enhance microglia numbers. This intermediary approach avoids complex procedural modifications while achieving substantial increases in human microglia quantity and distribution throughout the brain.
Data Source
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AI summary
The present invention provides a non-human animal having human interleukin-34 (IL-34) in the body thereof; a method for producing a non-human animal having human microglia, which includes transplanting human CD34-positive hematopoietic stem cells into the non-human animal having human IL-34 in the body; and a method for producing human microglia, which includes obtaining human microglia from the non-human animal having human microglia.