Reprogramming cell fates by small molecules

ABSTRACT Reprogramming cell fates towards pluripotent stem cells and other cell types has revolutionized our understanding of cellular plasticity. During the last decade, transcription factors and microRNAs have become powerful reprogramming factors for modulating cell fates. Recently, many efforts are focused on reprogramming cell fates by non-viral and non-integrating chemical approaches. Small molecules not only are useful in generating desired cell types in vitro for various applications, such as disease modeling and cell-based transplantation, but also hold great promise to be further developed as drugs to stimulate patients’ endogenous cells to repair and regenerate in vivo. Here we will focus on chemical approaches for generating induced pluripotent stem cells, neurons, cardiomyocytes, hepatocytes and pancreatic β cells. Significantly, the rapid and exciting advances in cellular reprogramming by small molecules will help us to achieve the long-term goal of curing devastating diseases, injuries, cancers and aging

Chemical Strategies for Stem Cell Biology and Regenerative Medicine

Stem cell technology holds great promises for the cures of devastating diseases, injuries, aging, and even cancers as it is applied in regenerative medicine. Recent breakthroughs in the development of induced pluripotent stem cell techniques and efficient differentiation strategies have generated tremendous enthusiasm and efforts to explore the therapeutic potential of stem cells. Small molecules, which target specific signaling pathways and/or proteins, have been demonstrated to be particularly valuable for manipulating cell fate, state, and function. Such small molecules not only are useful in generating desired cell types in vitro for various applications but also could be further developed as conventional therapeutics to stimulate patients' endogenous cells to repair and regenerate in vivo. Here, we focus on recent progress in the use of small molecules in stem cell biology and regenerative medicine. </jats:p

Direct Reprogramming of Adult Human Fibroblasts to Functional Neurons under Defined Conditions

SummaryHuman induced pluripotent stem cells (hiPSCs) have been generated by reprogramming a number of different somatic cell types using a variety of approaches. In addition, direct reprogramming of mature cells from one lineage to another has emerged recently as an alternative strategy for generating cell types of interest. Here we show that a combination of a microRNA (miR-124) and two transcription factors (MYT1L and BRN2) is sufficient to directly reprogram postnatal and adult human primary dermal fibroblasts (mesoderm) to functional neurons (ectoderm) under precisely defined conditions. These human induced neurons (hiNs) exhibit typical neuronal morphology and marker gene expression, fire action potentials, and produce functional synapses between each other. Our findings have major implications for cell-replacement strategies in neurodegenerative diseases, disease modeling, and neural developmental studies

Citric acid-driven cadmium uptake and growth promotion mechanisms in Brassica napus

Citric acid (CA) is well-known for mitigating cadmium (Cd) toxicity in plants. Yet, the underlying mechanisms driving growth promotion, Cd detoxification/tolerance, and enhanced phytoremediation processes remain incompletely understood. This study investigated the effects of CA application (2.5 mM) on Brassica napus grown in Cd-contaminated (30 mg kg−1) growth medium through a controlled pot experiment. Cd exposure alone significantly impaired various plant physiological parameters in B. napus. Whereas CA application significantly (p < 0.05) enhanced physiological attributes, Cd detoxification and tolerance by modulating key genes involved in photosynthesis and Cd transport, including the metal-transporting P1B-type ATPases (Cd/zinc heavy metal-transporting ATPase 1; HMA1) and light-harvesting chlorophyll a/b-binding 3 (LHCB3). Notably, CA application increased Cd accumulation in stems and leaves by 4% and 35%, respectively, enhancing bioconcentration factors (BCF) by 12% in stems and 40% in leaves while reducing root BCF by 10%. This translocation was facilitated by the upregulation of HMA4, HMA2, and plant Cd resistance (PCR2) genes in plant leaves, improving Cd mobility within the plant. Furthermore, CA induced a 34% increase in phytochelatins and a 32% upregulation in metallothioneins, accompanied by a significant reduction in oxidative stress markers, including a 40% decrease in hydrogen peroxide and a 44% decline in malondialdehyde levels in leaves. Enhanced antioxidant enzyme activity and osmolyte accumulation further contributed to improved Cd detoxification/sequestration in leaves, reduced oxidative stress, and improved photosynthetic efficiency, resulting in enhanced plant biomass production and Cd tolerance. Transcriptomic analysis showed that CA treatment substantially influenced the expression of 12,291 differentially expressed genes (DEGs), with 750 common genes consistently downregulated in CK vs Cd treatment group but upregulated in Cd vs Cd-CA treatment group. Additionally, CA modulated 11 DEGs associated with 32 gene ontologies in the citrate pathway under Cd stress, highlighting its targeted regulatory effect on metabolic pathways involved in Cd stress response. This study offers novel insights into the synergistic role of CA in promoting plant growth and regulating Cd uptake in B. napus, highlighting its potential to enhance phytoremediation strategies