Ureteric Bud-Like Tissue Induction via Staged Stem Cell Differentiation
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Solution Overview
Problem
There is a shortage of donor organs for kidney transplantation and a lack of effective treatments for chronic kidney disease, necessitating a method to efficiently produce kidney cells and tissues from pluripotent stem cells, particularly iPS cells, to address this issue and facilitate kidney development research and drug evaluation.
Innovation Solution
A method involving specific growth factors and inhibitors is employed to induce differentiation of pluripotent stem cells into ureteric bud-like tissues, including anterior primitive streak cells, anterior intermediate mesoderm cells, and Wolffian duct cells, through two-dimensional and suspension culture conditions, with cryopreservation and expansion-culturing techniques.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If kidney transplantation is performed to treat chronic kidney disease, then curative treatment is achieved, but severe shortage of donor organs limits its availability
Solution Approach 1:
The patent creates artificial kidney structures by guiding pluripotent stem cells to self-organize into kidney organoids that replicate the functional architecture of natural kidneys, including nephrons and collecting ducts. This copying approach generates unlimited supplies of kidney tissue for transplantation without requiring donor organs.
Solution Approach 2:
The patent employs a multi-stage differentiation protocol that segments the complex process of kidney formation into distinct phases: establishing intermediate mesoderm, forming Wolffian duct structures, and generating collecting duct epithelium. This segmentation enables systematic control and optimization of each developmental stage to produce functional kidney tissue.
2Productivity
If methods are developed to produce kidney cells from iPS cells, then donor organ shortage can be addressed, but the differentiation process into specific kidney cell types is not yet established
Solution Approach 1:
The patent uses preliminary action by first establishing intermediate mesoderm cells from pluripotent stem cells, then sequentially guiding them through Wolffian duct formation before final collecting duct differentiation. This staged preliminary action simplifies the overall complex process by breaking it into manageable steps with defined transition points.
Solution Approach 2:
The patent applies parameter changes by systematically varying culture conditions including specific growth factors (BMP4, FGF9, WNT3A), small molecule inhibitors (SB431542, LDN193189, IWR-1), and extracellular matrix compositions at each differentiation stage to drive cells through the complex differentiation pathway efficiently.
3Adaptability or versatility
If ureteric bud-like tissue is induced from pluripotent stem cells, then kidney tissue remodeling is enabled, but the method for selective differentiation into ureteric bud cells has not been known
Solution Approach 1:
The patent uses intermediary structures by first forming Wolffian duct-like tissues as intermediate structures that subsequently give rise to ureteric bud-like tissues. This intermediary approach provides a natural developmental bridge that simplifies the direct differentiation from pluripotent stem cells to functional kidney epithelium.
Solution Approach 2:
The patent segments the differentiation process into distinct phases with specific molecular signatures: intermediate mesoderm (OSR1+, GATA3+), Wolffian duct (RET+, GATA3+), and collecting duct (CK19+, GATA3+). This segmentation enables precise control and identification of each stage while managing the overall complexity of the differentiation protocol.
Data Source
AI summary
An object of the present application is to provide a method for inducing the differentiation from pluripotent stem cells, particularly iPS cells and ES cells, into ureteric bud cells. Another object of the present application is to provide a system for producing ureteric bud-like tissue from pluripotent stem cells through each stage of differentiations, i.e. anterior primitive streak cells, anterior intermediate mesoderm cells and Wolffian duct cells. Yet another object of the present application is to provide a method for maintaining ureteric bud-like organoids. Another object of the present application is to provide a method for expansion-culturing ureteric bud-like tip tissue.