Molecular hydrogen acts as a therapeutic agent in regenerative medicine by modulating stem cell activity, reducing oxidative stress, and promoting wound healing, particularly through its interaction with magnesium-based materials. Calcium and magnesium ions are crucial for stem cell differentiation and migration. In chemical and biological systems, hydrogen atom shifts, hydride shifts, and proton affinities (particularly related to transitional metals) are fundamental to energy production, catalysis, and molecular rearrangements.

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Molecular hydrogen (H2) acts as a therapeutic agent in regenerative medicine by modulating stem cell activity, primarily by reducing oxidative stress and acting on signaling pathways that govern stem cell proliferation and differentiation.
Magnesium (Mg2+) and Calcium (Ca2+) ions are critical in these processes, with (Mg2+) facilitating (H2) production in vivo through corrosion.

This hydrogen acts to alleviate oxidative stress (scavenging reactive oxygen species) and promotes the activation of epidermal and mesenchymal stem cells, accelerating tissue regeneration.

Molecular Hydrogen and Stem Cell Regeneration

Stem Cell Activation: Molecular hydrogen (66% H2+ 33% O2) has been shown to accelerate epidermal stem cell proliferation, inducing earlier re-epithelialization in wound healing models.

Mesenchymal Stem Cell (MSC) Priming: H2 acts as a protective, anti-inflammatory agent, enhancing the viability, engraftment, and differentiation potential of MSCs in regenerative therapies.

Mitochondrial Function: H2 improves stem cell energy metabolism by maintaining mitochondrial integrity and increasing ATP synthesis.

Signaling Pathways: Molecular Hydrogen H2 administration inhibits inflammatory markers (like NLRP3 and NF-B) and induces the expression of anti-inflammatory cytokines.

Role of Magnesium and Calcium in Regeneration
Alloy Degradation: Magnesium alloys act as continuous in vivo generators of hydrogen gas, creating a "hydrogen-rich cavity" that promotes local stem cell differentiation.

Signal Regulation: Extracellular Calcium Ca2+ levels modulate the proliferation and migration of mesenchymal stem cells (MSCs) to damaged tissue, aiding in repair.

Structural Regulation: Magnesium and Calcium are vital for tissue-specific differentiation (osteogenesis) and maintain the structural integrity of the extracellular matrix.

Molecular Mechanisms
Hydrogen Atom Transfer (HAT): HAT pathways are crucial in biological redox reactions, where transition metals (like iron or copper) form high-valent species that abstract hydrogen atoms from C(sp3) H bonds in proteins or drugs, enabling their modification.

Hydride Shifts: In chemical transformations, such as the synthesis of Vitamin D3, 1,7-hydride shifts (sigmatropic rearrangement) are essential, often catalyzed by UV light, which helps in calcium homeostasis.

Pericyclic Reactions: These concerted rearrangements involve cyclic transition states (sigmatropic shifts, electrocyclic reactions) to alter the structure of heterocyclic and organic compounds, essential in enzymatic catalysis.

Methylation/Methyl Donors: Methylation, a form of epigenetic regulation, plays a major role in the differentiation of stem cells, with hydrogen contributing indirectly by alleviating oxidative stress that can cause aberrant DNA modification.