Urolithin A Epigenetic Modification for HSPC Function

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Solution Overview

Problem

There is a significant need for additional approaches to increase stem cell function in haematopoietic stem and progenitor cells (HSPCs) for long-term engraftment and self-renewal, particularly during haematopoietic stem cell transplant procedures, as existing methods do not effectively sustain stem cell functionality beyond short-term improvements.

Innovation Solution

The use of urolithin A (UroA) to increase stem cell function in HSPCs by affecting their epigenetic signature, leading to enhanced engraftment, self-renewal, and differentiation capabilities, with sustained effects for at least 40 weeks, either in vitro or ex vivo, and administered orally or parenterally for therapeutic applications.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If artificial lowering of mitochondrial membrane potential is used to maintain HSC functionality, then stem cell function is improved under culture conditions, but the effect does not sustain long-term engraftment and self-renewal in vivo

Engineering Contradiction:

Improvestem cell functionVSAvoidduration of stem cell function increase

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent applies parameter changes by modifying the chemical structure from nicotinamide riboside to urolithin A, which fundamentally alters how mitochondrial membrane potential is lowered. Urolithin A achieves more sustained epigenetic modifications and metabolic reprogramming, transforming the temporary effect into a long-lasting effect that persists for at least 40 weeks in vivo, thereby resolving the contradiction between improving stem cell function and sustaining its duration.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

Urolithin A acts as an intermediary compound that mediates between the initial chemical treatment and the long-term epigenetic changes in HSCs. It facilitates sustained mitochondrial membrane potential lowering and triggers persistent epigenetic reprogramming, serving as a bridge that converts short-term chemical exposure into long-term functional improvement, thus resolving the duration limitation of previous approaches.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If nicotinamide riboside is supplemented to lower mitochondrial membrane potential, then engraftment levels are increased, but the effect is limited in duration and requires continuous supplementation

Engineering Contradiction:

ImproveengraftmentVSAvoidduration of engraftment improvement

Core Design Contradiction:

ReliabilityVSDuration of action of stationary object

Solution Approach 1:

The patent changes the chemical parameter from nicotinamide riboside to urolithin A, which produces more persistent epigenetic modifications. This parameter change transforms the transient engraftment improvement into a sustained effect lasting at least 40 weeks, resolving the contradiction between achieving high engraftment and maintaining it long-term without continuous supplementation.

Inventive Principle:

Principle #35Parameter changes

3Reliability

If HSCs rely on anaerobic glycolysis to protect from ROS damage, then long-term in vivo function is maintained, but the capacity for self-renewal and differentiation is limited

Engineering Contradiction:

Improveprotection from ROS damageVSAvoidself-renewal and differentiation capacity

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

Urolithin A induces parameter changes in mitochondrial function and epigenetic state that allow HSCs to transiently modulate their metabolic profile. This triggers epigenetic reprogramming that enhances self-renewal and differentiation capacity while maintaining protection mechanisms, resolving the contradiction between ROS protection and productive capacity by enabling dynamic metabolic adaptation rather than fixed reliance on glycolysis.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent introduces dynamics by enabling HSCs to flexibly adjust their metabolic and epigenetic state in response to urolithin A treatment. Rather than being statically locked into anaerobic glycolysis, the cells can dynamically modulate mitochondrial membrane potential and epigenetic marks to balance ROS protection with enhanced self-renewal and differentiation capacity, resolving the contradiction between protective quiescence and active productivity.

Inventive Principle:

Principle #15Dynamics

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

UroA treatment significantly enhances stem cell function, including engraftment and self-renewal, with prolonged effects of at least 40 weeks, improving blood cell production and immune cell function, and can be used to treat conditions such as anaemia, leukopenia, and cancer by increasing blood cell levels and immune cell production.

Implementation Method 1

affecting their epigenetic signature

Methodology Applied

Scientific EffectEpigenetic modification:

Data Source

PatentUS20240228966A1Urolithin for increasing stem cell function

Publication Date: 2024.07.11 SOCIETE DES PRODUITS NESTLE SA

AI summary

Use of a urolithin for increasing stem cell function in a population of haematopoietic stem and/or progenitor cells (HSPCs), wherein the stem cell function is increased for at least 40 weeks.