RESUMEN
Bone marrow mesenchymal stem cells (BM-MSCs) are promising candidates for regenerative medicine purposes. The effect of obesity on the function of BM-MSCs is currently unknown. Here, we assessed how obesity affects the function of BM-MSCs and the role of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) therein. BM-MSCs were obtained from healthy donors with a normal (<25) or high (>30) body mass index (BMI). High-BMI BM-MSCs displayed severely impaired osteogenic and diminished adipogenic differentiation, decreased proliferation rates, increased senescence, and elevated expression of ER stress-related genes ATF4 and CHOP. Suppression of ER stress using tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyrate (4-PBA) resulted in partial recovery of osteogenic differentiation capacity, with a significant increase in the expression of ALPL and improvement in the UPR. These data indicate that BMI is important during the selection of BM-MSC donors for regenerative medicine purposes and that application of high-BMI BM-MSCs with TUDCA or 4-PBA may improve stem cell function. However, whether this improvement can be translated into an in vivo clinical advantage remains to be assessed.
Asunto(s)
Índice de Masa Corporal , Estrés del Retículo Endoplásmico/genética , Células Madre Mesenquimatosas/metabolismo , Obesidad/metabolismo , Factor de Transcripción Activador 4/genética , Adipogénesis/efectos de los fármacos , Adolescente , Adulto , Fosfatasa Alcalina/genética , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Senescencia Celular/efectos de los fármacos , Niño , Femenino , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/patología , Persona de Mediana Edad , Obesidad/genética , Obesidad/patología , Osteogénesis/efectos de los fármacos , Fenilbutiratos/farmacología , Medicina Regenerativa , Ácido Tauroquenodesoxicólico/farmacología , Donantes de Tejidos , Factor de Transcripción CHOP/genética , Respuesta de Proteína Desplegada/genética , Adulto JovenRESUMEN
This chapter introduces the increasing significance of mesenchymal stromal/stem cell (MSC) production in regenerative medicine and cellular therapeutics, outlines the growing interest in MSCs for various medical applications, and highlights their potential in advanced therapy medicinal products (ATMPs) and the advancements in cell culture technologies that have facilitated large-scale MSC production under Good Manufacturing Practices (GMP), ensuring safety and efficacy. This chapter describes an optimized upstream protocol for laboratory-scale MSC production from different tissue sources. This protocol, conducted in flasks, controls critical parameters and lays the foundation for downstream processing to generate ATMPs. This comprehensive approach underscores the potential of MSCs in clinical applications and the importance of tailored production processes.