# Tendon Organoids Enable Functional Tendon Rejuvenation Through ALKBH5‐Dependent RNA Demethylation

## TL;DR

Researchers created fetal-like tendon organoids from adult cells, which can regenerate tendon structure and function, offering a new approach for treating tendon injuries.

## Contribution

The study introduces fetal-like tendon organoids with regenerative capacity and identifies ALKBH5 as a key demethylase in tendon regeneration.

## Key findings

- Fetal-like tendon organoids were generated from adult TSPCs using a 3D culture system.
- Transplantation of these organoids led to functional tendon collagen matrix regeneration in vivo.
- ALKBH5-dependent RNA demethylation activates TGF-β signaling for tendon regeneration.

## Abstract

Adult tendon injuries pose a major clinical challenge due to limited self‐repair capacity, resulting in suboptimal regeneration. Although tendon stem/progenitor cells (TSPCs) are pivotal for tendon engineering, achieving microstructure and functional regeneration remains challenging. Organoids boost tissue regeneration post‐transplantation in multiple organs. however, tendon‐specific organoids with stable phenotype and regenerative capacity are still lacking. Since fetal tendons possess strong regenerative capabilities, the construction of fetal‐like tendon organoids is crucial for promoting tendon regeneration. In this study, we generated fetal‐like tendon organoids (FT organoids) from adult TSPCs using a serum‐free 3D culture system that recapitulated the in vivo microenvironment. These organoids exhibited robust phenotypic restoration and enhanced tenogenic potential, with a gene expression profile resembling fetal tendon development. Notably, transplantation experiments demonstrated functional regeneration of organized tendon collagen matrices in vivo. Furthermore, the mRNA demethylase ALKBH5 plays a critical role in activating key regulatory networks for tendon regeneration via the TGF‐β signaling pathway. These findings provided compelling evidence that FT organoids represent a promising strategy for tendon collagen microstructure regeneration and highlights their promising clinical translation potential.

FT organoids reverse the aged phenotype of tendon cells, reinstating a fetal‐like state. This breakthrough establishes a potent cell source for tendon tissue engineering, effectively advancing regenerative medicine.