A novel dental stem cell-based in vitro model for x-linked adrenoleukodystrophy: from development to therapeutic strategies

• Autores: Claudia Pérez García
• Directores de la Tesis: Salvador Martínez Perez (dir. tes.)
• Lectura: En la Universidad Miguel Hernández de Elche ( España ) en 2025
• Idioma: español
• Tribunal Calificador de la Tesis: José María Moraleda Jiménez (presid.), Raquel Garcia Lopez (secret.), Fernando de Castro Soubriet (voc.)
• Programa de doctorado: Programa de Doctorado en Neurociencias por la Universidad Miguel Hernández de Elche
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• Resumen

  • X-linked adrenoleukodystrophy (X-ALD) is a rare genetic disorder caused by mutations in the ABCD1 gene. This gene encodes the adrenoleukodystrophy protein (ALDP), a crucial peroxisomal membrane protein responsible for transporting very long-chain fatty acids (VLCFAs) into peroxisomes, where these fatty acids are broken down. In X-ALD, mutations in ABCD1 lead to a malfunction in ALDP, resulting in the accumulation of VLCFAs in the body, particularly in the nervous system and adrenal tissues. This accumulation causes a spectrum of clinical manifestations that range from adrenal insufficiency to severe neurodegenerative symptoms, including inflammatory demyelination of the central nervous system, leading to debilitating and often fatal outcomes. The complexity and variability of symptoms, alongside limited therapeutic options, make X-ALD particularly challenging to treat, especially for patients with the most severe forms of the disease. One of the primary obstacles in understanding X-ALD's underlying mechanisms and developing targeted treatments is the absence of effective animal models that accurately mimic the demyelination process observed in humans. As a result, researchers have turned to human cell-based models to study the disease.

    In this Doctoral Thesis, we sought to advance the understanding of X-ALD through the development of a novel in vitro model using human dental pulp stem cells (hDPSCs) derived from an affected patient. These cells provide a unique and clinically relevant model, as they express the ALDP protein similarly to cells from healthy individuals, but exhibit abnormal neutral lipid accumulation, reflecting the dysfunction of ALDP seen in X-ALD. This model is particularly promising because hDPSCs have natural neurogenic potential, meaning they can differentiate into neural-like cells that are capable of mimicking the pathological features of the disease, including increased neutral lipid accumulation, which is observed in the cellular bodies of differentiated neural lineage cells. In addition, impairments in sodium channel currents are also evidenced in X-ALD differentiated cells, suggesting an alteration in the process of functional neural differentiation. These characteristics make hDPSCs a valuable resource for studying X-ALD's pathophysiology and testing potential therapeutic interventions. In addition to this model, we also have highlighted the therapeutic potential of human bone marrow derived mesenchymal stem cells (hBMSCs).The findings reveal that conditioned media (CM) from hBMSCs, containing EVs, can mitigate the abnormal lipid accumulation observed in X-ALD hDPSCs. Furthermore, hBMSCs protect these cells from oxidative stress and from cytotoxic effects derived from VLCFA, a condition that exacerbates cellular damage in many neurodegenerative diseases, including X-ALD. In addition to this paracrine signaling, hBMSCs also establish direct cellular communication with X-ALD hDPSCs. This direct interaction enables the transfer of healthy mitochondria and other cytosolic components from hBMSCs to the affected cells, which may help restore cellular function and potentially revert the diseased phenotype.Furthermore, through the establishment of cell-to-cell contacts, hBMSCs induce changes in sodium channel pattern of X-ALD differentiated cells, rescuing a healthy phenotype.

    The combined actions of direct cell-to-cell contact and indirect (paracrine) signaling suggest that hBMSCs hold significant therapeutic promise for treating X-ALD. Their ability to not only protect but also potentially correct the pathological features of the disease at the cellular level represents a substantial advancement in X-ALD research. This doctoral thesis highlights the potential of hBMSCs and cell-derived products as a therapeutic tool for X-ALD.

    Through the advancement in human cell models and therapeutic strategies, this thesis aims to enhance the understanding of the disease and opens new avenues for developing effective therapies.