All-trans retinoic acid induces reprogramming of canine dedifferentiated cells into neuron-like cells.
Rei NakanoTaku KitanakaShinichi NambaNanako KitanakaMasaki SatoYoshiyuki ShibukawaYoshikazu MasuhiroKoichiro KanoTaro MatsumotoHiroshi SugiyaPublished in: PloS one (2020)
The specification of cell identity depends on the exposure of cells to sequences of bioactive ligands. All-trans retinoic acid (ATRA) affects neuronal development in the early stage, and it is involved in neuronal lineage reprogramming. We previously established a fibroblast-like dedifferentiated fat cells (DFATs) derived from highly homogeneous mature adipocytes, which are more suitable for the study of cellular reprogramming. Canine cognitive dysfunction is similar to human cognitive dysfunction, suggesting that dogs could be a pathological and pharmacological model for human neuronal diseases. However, the effect of ATRA on neuronal reprogramming in dogs has remained unclear. Therefore, in this study, we investigated the effect of ATRA on the neuronal reprogramming of canine DFATs. ATRA induced the expression of neuronal marker mRNA/protein. The neuron-like cells showed Ca2+ influx with depolarization (50 mM KCl; 84.75 ± 4.05%) and Na+ channel activation (50 μM veratridine; 96.02 ± 2.02%). Optical imaging of presynaptic terminal activity and detection of neurotransmitter release showed that the neuron-like cells exhibited the GABAergic neuronal property. Genome-wide RNA-sequencing analysis shows that the transcriptome profile of canine DFATs is effectively reprogrammed towards that of cortical interneuron lineage. Collectively, ATRA can produce functional GABAergic cortical interneuron-like cells from canine DFATs, exhibiting neuronal function with > 80% efficiency. We further demonstrated the contribution of JNK3 to ATRA-induced neuronal reprogramming in canine DFATs. In conclusion, the neuron-like cells from canine DFATs could be a powerful tool for translational research in cell transplantation therapy, in vitro disease modeling, and drug screening for neuronal diseases.
Keyphrases
- single cell
- induced apoptosis
- cerebral ischemia
- early stage
- genome wide
- endothelial cells
- cell cycle arrest
- emergency department
- gene expression
- stem cells
- rna seq
- signaling pathway
- dna methylation
- oxidative stress
- type diabetes
- bone marrow
- high glucose
- small molecule
- poor prognosis
- radiation therapy
- subarachnoid hemorrhage
- endoplasmic reticulum stress
- metabolic syndrome
- skeletal muscle
- blood brain barrier
- cell proliferation
- pi k akt
- amino acid
- fluorescence imaging
- diabetic rats
- quantum dots
- protein protein
- high speed
- atomic force microscopy