Abstract
Transcription factors and signaling molecules are well-known regulators of stem cell identity and behavior; however, increasing evidence indicates that environmental cues contribute to this complex network of stimuli, acting as crucial determinants of stem cell fate. l-Ascorbic acid (vitamin C (VitC)) has gained growing interest for its multiple functions and mechanisms of action, contributing to the homeostasis of normal tissues and organs as well as to tissue regeneration. Here, we review the main functions of VitC and its effects on stem cells, focusing on its activity as cofactor of Fe+2/αKG dioxygenases, which regulate the epigenetic signatures, the redox status, and the extracellular matrix (ECM) composition, depending on the enzymes' subcellular localization. Acting as cofactor of collagen prolyl hydroxylases in the endoplasmic reticulum, VitC regulates ECM/collagen homeostasis and plays a key role in the differentiation of mesenchymal stem cells towards osteoblasts, chondrocytes, and tendons. In the nucleus, VitC enhances the activity of DNA and histone demethylases, improving somatic cell reprogramming and pushing embryonic stem cell towards the naive pluripotent state. The broad spectrum of actions of VitC highlights its relevance for stem cell biology in both physiology and disease.
Highlights
L-Ascorbic acid (vitamin C (VitC)) was extensively studied over the last century because it plays an essential role for proper folding and deposition of collagen proteins, which are the most abundant proteins in the human body and have a strong impact on the composition/structure/biomechanical features of the extracellular matrix (ECM)
Scurvy is characterized by a generalized tissue disintegration, dissolution of intercellular ECM, which induces an excessive proliferation of undifferentiated cells and a reversion to a primitive form of the tissue [137]
An increasing number of reports reveal that VitC impacts on stem cell plasticity/identity and that this largely depends on its ability to sustain the activity of several Fe+2/αKG dioxygenase enzymes, which catalyze the hydroxylation of different biological substrates located in specific cellular compartments
Summary
L-Ascorbic acid (vitamin C (VitC)) was extensively studied over the last century because it plays an essential role for proper folding and deposition of collagen proteins, which are the most abundant proteins in the human body and have a strong impact on the composition/structure/biomechanical features of the extracellular matrix (ECM). Human cells are unable to synthesize VitC, and it must constantly be restored through the diet. It is only until recently that ECM homeostasis was considered the unique molecular mechanism influenced by VitC availability. VitC has emerged as a key regulator of stem cell identity/behavior, influencing pluripotency, self-renewal, and differentiation. The strong biological, biotechnological, and medical significance of VitC-dependent molecular mechanisms become even more relevant taking into account another key VitC-dependent cellular modification, that is, collagen hydroxylation, which is the most abundant posttranslation modification found in the human proteoma. We will focus on the recent progress made on the influence of VitC on stem cell biology and its implications for regenerative medicine
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