LIN28A enhances regenerative capacity of human somatic tissue stem cells via metabolic and mitochondrial reprogramming

Developing methods to improve the regenerative capacity of somatic stem cells (SSCs) is a major challenge in regenerative medicine. Here, we propose the forced expression of LIN28A as a method to modulate cellular metabolism, which in turn enhances self-renewal, differentiation capacities, and engraftment after transplantation of various human SSCs. Mechanistically, in undifferentiated/proliferating SSCs, LIN28A induced metabolic reprogramming from oxidative phosphorylation (OxPhos) to glycolysis by activating PDK1-mediated glycolysis-TCA/OxPhos uncoupling. Mitochondria were also reprogrammed into healthy/fused mitochondria with improved functional capacity. The reprogramming allows SSCs to undergo cell proliferation more extensively with low levels of oxidative and mitochondrial stress. When the PDK1-mediated uncoupling was untethered upon differentiation, LIN28A-SSCs differentiated more efficiently with an increase of OxPhos by utilizing the reprogrammed mitochondria. This study provides mechanistic and practical approaches of utilizing LIN28A and metabolic reprogramming in order to improve SSCs utility in regenerative medicine.

Automated summary

Forced expression of LIN28A modulates cellular metabolism, enhancing the self-renewal and differentiation capacities of human SSCs. The metabolic reprogramming induced by LIN28A leads to improved functional capacity of mitochondria and allows for extensive cell proliferation with low levels of stress. This study provides mechanistic and practical approaches to enhance SSCs utility in regenerative medicine through LIN28A and metabolic reprogramming.