hiPSC-Derived BBB Model with Mature Immune Phenotype

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Solution Overview

Problem

Current human-induced pluripotent stem cell (hiPSC)-derived blood-brain barrier models lack a mature immune phenotype, specifically expressing key adhesion molecules involved in immune cell migration across the blood-brain barrier, which is crucial for studying neuroinflammatory and neurodegenerative diseases.

Innovation Solution

The extended endothelial cell culture method (EECM) differentiates hiPSC-derived endothelial progenitor cells into brain microvascular endothelial cells (BMECs) with a mature immune phenotype, expressing ICAM-1, ICAM-2, E-selectin, and other adhesion molecules, and displaying barrier properties similar to primary human brain endothelial cells, using a protocol involving serum-free endothelial medium and collagen-coated surfaces.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If human induced pluripotent stem cell (hiPSC)-derived blood-brain barrier models are used, then scalability and renewability are improved, but the expression of key adhesion molecules involved in immune cell migration is insufficient

Engineering Contradiction:

Improvescalability and renewabilityVSAvoidexpression of adhesion molecules

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent applies parameter changes by modifying culture conditions including serum-free endothelial medium, collagen-coated surfaces, and specific passage protocols to induce the expression of adhesion molecules (ICAM-1, ICAM-2, E-selectin, VCAM-1) in hiPSC-derived BMECs while maintaining their barrier properties and scalability

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent uses preliminary action by pre-differentiating hiPSCs into endothelial progenitor cells before further differentiation into BMECs, and by pre-coating culture surfaces with collagen to prepare the microenvironment that promotes adhesion molecule expression before immune cell interaction studies

Inventive Principle:

Principle #10Preliminary action

2Ease of manufacture

If conventional hiPSC-derived BBB models are used, then ease of manufacture is improved, but the mature immune phenotype is lacking

Engineering Contradiction:

Improveease of manufactureVSAvoidmature immune phenotype

Core Design Contradiction:

Ease of manufactureVSManufacturing precision

Solution Approach 1:

The patent applies segmentation by dividing the differentiation process into distinct stages: hiPSC → endothelial progenitor cells → BMECs with mature immune phenotype, allowing each stage to be optimized independently while maintaining overall ease of manufacture and achieving the desired mature immune phenotype

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent uses an intermediary approach by introducing endothelial progenitor cells as an intermediate stage between hiPSCs and mature BMECs, and by using collagen-coated surfaces as an intermediary that mediates the development of mature immune phenotype through appropriate cell-matrix interactions

Inventive Principle:

Principle #24Intermediary (Mediator)

3Ease of operation

If human brain endothelial cell lines are used, then availability is improved, but barrier properties with high transendothelial electrical resistance and low permeability are not established

Engineering Contradiction:

ImproveavailabilityVSAvoidbarrier properties

Core Design Contradiction:

Ease of operationVSReliability

Solution Approach 1:

The patent applies parameter changes by optimizing culture conditions including serum-free medium composition, collagen coating density, passage timing, and cell density to simultaneously achieve high availability of the cell model and reliable barrier properties characterized by high transendothelial electrical resistance and low permeability

Inventive Principle:

Principle #35Parameter changes

4Reliability

If primary human brain microvascular endothelial cells are used, then utility for studying T-cell/BBB interactions is improved, but availability and scalability are reduced

Engineering Contradiction:

Improveutility for studying T-cell/BBB interactionsVSAvoidavailability and scalability

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent applies copying by creating hiPSC-derived BMECs that replicate the key functional properties of primary human brain microvascular endothelial cells, including adhesion molecule expression patterns and T-cell interaction capabilities, while providing unlimited scalability and availability through stem cell differentiation

Inventive Principle:

Principle #26Copying

Data Source

PatentUS20230375530A1Human blood-brain barrier model for immunological studies

Publication Date: 2023.11.23 UNIVERSITY OF BERN

AI summary

The present invention provides methods for differentiating brain microvascular endothelial cells having barrier properties and a mature immune phenotype for use in making an in vitro blood-brain barrier (BBB) model. Further, a BBB model having barrier properties and a mature immune phenotype is provided.