Rapid and Efficient Conversion of Human Fibroblasts into Functional Neurons by Small Molecules

Abstract

SummaryRecent studies have demonstrated that human astrocytes and fibroblasts can be directly converted into functional neurons by small molecules. However, fibroblasts, as a potentially better cell resource for transplantation, are not as easy to reprogram as astrocytes regarding their fate to neurons, and chemically induced neurons (iNs) with low efficiency from fibroblasts resulted in limited application for the treatment of neurological disorders, including depression. Here, we report that human fibroblasts can be efficiently and directly reprogrammed into glutamatergic neuron-like cells by serially exposing cells to a combination of small molecules. These iNs displayed neuronal transcriptional networks, and also exhibited mature firing patterns and formed functional synapses. Importantly, iNs could integrate into local circuits after transplantation into postnatal mouse brain. Our study provides a rapid and efficient transgene-free approach for chemically generating neuron-like cells from human fibroblasts. Furthermore, our approach offers strategies for disease modeling and drug discovery in central nervous system disorders.

Direct Reprogramming of Somatic Cells to Neurons: Pros and Cons of Chemical Approach

“…For sure, fibroblasts are better starting cells for direct neuronal reprogramming because of easier access for acquisition than astrocytes, although their lower reprogramming efficiency to neurons needs to be increased for broader application in neurological diseases. For example, Yang et al reported that human fibroblasts can be efficiently and directly reprogrammed into glutamatergic neurons by serially exposing cells to a combination of twelve small molecules [ 59 ]. These ciNs displayed neuronal transcriptional networks, and also exhibited mature firing patterns and formed functional synapses.…”

Research Progress on Tissue Engineering of Main Tissues and Organs of Human Body

“…At present, totipotent stem cells, pluripotent stem cells and directional stem cells are the most important seed cells in tissue engineering research. In addition to stem cells, transdifferentiation or lineage reprogramming can also transform endothelial cells [8], epithelial cells [9], fibroblast [10][11][12][13], muscle cells [14], tendon cells [15], hepatocyte [16] and other differentiated cells with limited ability to divide into other types of functional cells or progenitor cells, and use them for tissue engineering research. Duncan et al [17] differentiated induced pluripotent stem cells into hepatocytes by adding five growth factors.…”

Small Molecule Epigenetic Modulators in Pure Chemical Cell Fate Conversion

“…In 2019, Dai's research group found a rapid and efficient method to convert human fibroblasts into neurons with twelve small molecules (CHIR99021, LDN193189, Dorsomorphin, ISX9, RG108, PD0325901, Purmorphamine, DAPT, Forskolin, ISX9, Y-27632, and P7C3) [ 42 ].…”