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Stem cell proliferation and differentiation

Stem cells have garnered significant attention in biomedical research due to their unique capacity for self-renewal and differentiation into various cell types. The manipulation of stem cell behavior through natural substances, metabolites, and drugs has become a promising strategy to influence their proliferation and differentiation. This approach holds substantial clinical implications, particularly in the realms of organ regeneration, cancer treatment and therapies for neurodegenerative diseases. The mechanisms underlying stem cell proliferation and differentiation are regulated by complex interactions involving protein kinases, transcription factors and epigenetic modifications.

  • Protein Kinases: Protein kinases play a pivotal role in signal transduction pathways that control cell cycle progression and differentiation. Key protein kinases such as extracellular signal-regulated kinases (ERK), phosphoinositide 3-kinase (PI-3K), and AKT are involved in promoting stem cell proliferation by transmitting growth signals. The Wnt/β-catenin pathway, which is mediated by glycogen synthase kinase-3β (GSK-3β), is essential for maintaining stem cell pluripotency and directing differentiation. Dysregulation of these kinase pathways can lead to impaired cell fate decisions or uncontrolled proliferation.
  • Transcription Factors: Transcription factors such as Oct-4, Sox2, and Nanog are critical for maintaining stem cell pluripotency. These factors work synergistically to activate genes that support self-renewal while repressing differentiation-associated genes. During differentiation, lineage-specific transcription factors, including MyoD for muscle cells and NeuroD1 for neurons, are upregulated to drive cells toward specific fates. The balance between these pluripotency and lineage-specific factors is essential for proper stem cell function.
  • Epigenetic Regulation: Epigenetic modifications, including DNA methylation and histone modifications, play a crucial role in controlling gene expression during stem cell proliferation and differentiation. For instance, DNA methyltransferases (DNMTs) add methyl groups to cytosine residues, typically silencing gene expression, while histone acetyltransferases (HATs) promote transcriptional activation by acetylating histones and loosening chromatin structure. Non-coding RNAs, such as microRNAs (miRNAs), also contribute to post-transcriptional regulation of gene expression, influencing the stability and translation of mRNAs critical for stem cell maintenance and differentiation.

Modulating the signaling: from the surface to the core

The proliferation and differentiation of stem cells can be modulated by specific biochemical cues. Natural substances, such as curcumin, resveratrol and certain flavonoids, have shown potential in enhancing stem cell growth and directing their lineage commitment. Scientists have tested polyphenols like ferulic acid, resveratrol, polydatin, oleuropein and EGCG from gree tea. This last substance is a protein kinase inhibitor and a modulator of DNA-C-methyltransferase (DNMT-1). Also flavonoids like apigenin, genistein, baicalein, chrisin and naringenin have proven to affect either the proliferative and maturative potential of cultured stem cells. They affect protein tyrosine-kinases and MAP-kinase members like JNK and p38 involved in cellular differentiation.

Stem cells also possess hormone receptors of the steroid/thyroid superfamily, like ER-alpha and other related receptors (ERRs). They are sensitive to isoflavones like genistein and baicalein and ERR-alpha is involved in neural stem cell renewal. Therefore, it is to wonder whether vegetarians that consume a lot of soy (source of genisteins and daidzein) or legumes (osurces of baicalein) may be advantaged over regular omnivore people, thank to their isoflavone intake. While there is some evidence to suggest that plant-based diets can positively impact cognitive health and cellular processes, the claim that vegetarians definitively have better memory or enhanced stem cell renewal is still a topic of active research and debate.

Metabolism is everything: and stem cells rely on basic molecules

Recent progress has led to a significant advance in the understanding of the transcriptional networks that regulate different stem cell states, while improvements in genome/transcriptome sequencing have greatly enhanced our comprehension of the role played by epigenetic regulators in this process. However, work over the last several years has identified an essential role for metabolites in the regulation of epigenetics and transcription, including S-adenosyl methionine (SAM) produced via the one-carbon cycle, acetyl-CoA from glycolysis, α–ketoglutarate (α-KG) and flavin adenine dinucleotide (FAD) from the mitochondrial TCA cycle, and NAD+ from the integration of glycolysis and mitochondrial oxidative phosphorylation.

The majority of mammalian cells (including primed PSCs) require glutamine for proliferation, as a source of nitrogen and to maintain TCA cycle intermediates. In primed PSCs the absence of glutamine has been found to lead to depleted α-KG levels, which in turn reduces the activity of histone demethylases and results in increased trimethylation of histone H4 lysines and subsequent differentiation. Interestingly, that naïve PSCs could proliferate and maintain histone demethylation in the absence of glutamine, through the utilization of glucose to maintain α-KG levels. Under this point of view, stem cells behave like cancer cells, which do not differentiate and utilize glutamine to enhance DNA base production and glutathione synthesis to protect themselves form oxidative stress.

Metabolites like nicotinamide adenine dinucleotide (NAD+) and α-KG play a crucial role in cellular metabolism and have been linked to improved stem cell function and rejuvenation. Also ascorbic acid (vitamin C) and vitamin D3 (active form) may affect stem cell maturation by affecting transcription and epigenetics. Ascorbic acid has been implicated as a cofactor in epigenetic regulation of mesenchimal stem cells by regulating JmjC histone demethylase and TET dioxygenases that catalyze the conversion of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC). Regulation of histone acetylation by cytoplasmic acetyl-CoA also seems to be an important determinant of the pluripotency. High glycolytic rates drive this process and have recently been shown to be critical for stem cell maintenance.

Consistent with this, glycolytic rates, acetyl-CoA levels and global histone acetylation decline during early differentiation. Vitamin D, on the contrary, as a lipophilic molecule, passes through the cellular membrane and binds the VDR in the nucleus. This complex forms a heterodimer with the Retinoid X Receptor (RXR), which is subsequently bound to the Vitamin-D-Responsive Elements (specific sequences of DNA in the promoter region of responsive genes), controlling their transcription. This way VD3 has been proved to regulate bone, cartilage and adipose tissue immature precurors into mature ones. In the brain, neural stem cells (NSCs) constitutively express VDR, which can be upregulated by VD3 itself. This vitamin significantly enhanced proliferation of NSCs, and enhanced their differentiation into neurons and oligodendrocytes, but not astrocytes.

Clinical implications for tissue regeneration

The ability to condition stem cell behavior has paved the way for regenerative medicine approaches to restore damaged tissues and organs. Stem cells conditioned by natural substances and growth-promoting drugs have been utilized in tissue engineering to develop bioartificial organs, which can potentially address the shortage of donor organs. The use of stem cells, particularly mesenchymal stem cells (MSCs) preconditioned with metabolites like hypoxia-inducible factors, has shown promise in regenerating myocardial tissue post-infarction. Research has highlighted the capacity of stem cells to differentiate into hepatocytes and nephron-like structures, when exposed to specific growth factors and metabolites, offering hope for patients with liver or kidney failure.

Neurodegenerative disease treatment

Neurodegenerative diseases, including Parkinson’s, Alzheimer’s, and amyotrophic lateral sclerosis (ALS), are characterized by the progressive loss of specific neuronal populations. The differentiation of pluripotent stem cells into dopaminergic neurons or other specific neuronal subtypes has provided a platform for potential cell-replacement therapies. Substances such as polyphenols and omega-3 fatty acids have been explored for their neuroprotective properties, which can enhance the survival and differentiation of transplanted stem cells in the brain. NAD+ precursors (nicotinamide and nicotinic acid riboside or NAR) and other mitochondrial-enhancing metabolites have been shown to improve the viability and function of neural stem cells, offering hope for slowing disease progression and promoting neural repair.

Therapeutic approaches for cancer

In oncology, the dual role of stem cells poses both opportunities and challenges. While stem cells can be used for tissue regeneration post-chemotherapy or radiotherapy, cancer stem cells (CSCs) contribute to tumorigenesis and therapy resistance. Modulating stem cell pathways with natural substances, such as quercetin and sulforaphane, has shown potential in selectively targeting CSCs to prevent tumor recurrence. Drugs that inhibit key signaling pathways in CSCs, such as Hedgehog, Notch, and PI3K/AKT/mTOR, are being investigated as adjuvant therapies to traditional cancer treatments. Additionally, the use of stem cell-based immunotherapies, where stem cells are engineered to express tumor-targeting antigens, is emerging as a novel strategy in cancer treatment.

Conclusion

The ability to condition stem cell proliferation and differentiation using natural substances, metabolites, and pharmacological agents has far-reaching clinical implications. These approaches not only provide solutions for organ regeneration but also introduce innovative therapeutic strategies for combating cancer and treating neurodegenerative diseases. Continued research and clinical trials are essential to translating these findings into effective therapies.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Bibliografia scientifica

Kumar A et al. (2023). Neurobiol Rep, 27(7), 300-315.

Sahu B et al. (2022). J Natural Prod, 85(3), 456-470.

Liu J et al. (2021). Cell Metabolism, 33(4), 678-693.

Smith DL et al. (2020). Cancer Res Rev78(10), 1125.

Calder PC et al. (2018). Neurosci Rev, 24(1), 17-30.

Dyall SC. (2015). Frontiers in Aging Neurosci, 7, 52.

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Dott. Gianfrancesco Cormaci
Dott. Gianfrancesco Cormaci
Laurea in Medicina e Chirurgia nel 1998; specialista in Biochimica Clinica dal 2002; dottorato in Neurobiologia nel 2006; Ex-ricercatore, ha trascorso 5 anni negli USA (2004-2008) alle dipendenze dell' NIH/NIDA e poi della Johns Hopkins University. Guardia medica presso la casa di Cura Sant'Agata a Catania. Medico penitenziario presso CC.SR. Cavadonna (SR) Si occupa di Medicina Preventiva personalizzata e intolleranze alimentari. Detentore di un brevetto per la fabbricazione di sfarinati gluten-free a partire da regolare farina di grano. Responsabile della sezione R&D della CoFood s.r.l. per la ricerca e sviluppo di nuovi prodotti alimentari, inclusi quelli a fini medici speciali.

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