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Psoralen Promotes Direct Chemical Reprogramming of Mouse Embryonic Fibroblasts into Osteoblast-like Cells.

Wenjie Li1, Haixia Liu1, Xinyu Wan1

  • 1Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China.

Pharmaceutics
|February 27, 2026
PubMed
Summary

Psoralen significantly enhances direct chemical reprogramming of cells into osteoblasts, improving bone regeneration. This natural compound activates a key signaling pathway, boosting the generation of functional bone-forming cells.

Keywords:
adenylyl cyclase 9bone regenerationcellular reprogrammingfibroblastspsoralen

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Area of Science:

  • Regenerative Medicine
  • Stem Cell Biology
  • Biomaterials Science

Background:

  • Direct chemical reprogramming offers a promising route to generate osteoblasts for bone regeneration.
  • Current methods require enhancement for improved efficiency and therapeutic efficacy.
  • Psoralen (Psr), a natural compound, was investigated for its potential to boost osteogenic reprogramming.

Purpose of the Study:

  • To evaluate psoralen's ability to enhance direct chemical reprogramming into osteoblast-like cells (ciOBs).
  • To assess the therapeutic potential of Psr-enhanced ciOBs for bone regeneration in vivo.
  • To elucidate the underlying molecular mechanism of Psr's pro-osteogenic effects.

Main Methods:

  • Mouse embryonic fibroblasts (MEFs) were treated with a reprogramming cocktail (FP) supplemented with psoralen.
  • In vitro osteogenic differentiation was assessed using biochemical and molecular assays.
  • In vivo bone regeneration was evaluated in calvarial and femoral defect models, and ectopic implantation sites.
  • The involvement of the adenylyl cyclase 9 (ADCY9)/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP response element-binding protein (CREB) pathway was investigated.

Main Results:

  • Psoralen synergistically enhanced FP-induced osteogenic reprogramming of MEFs.
  • Optimal psoralen concentration (25 μM) promoted robust in vitro osteoblast differentiation and mineralization.
  • FP + Psr-induced ciOBs effectively repaired critical-sized bone defects and formed vascularized bone tissue ectopically.
  • Psoralen activated the ADCY9/cAMP/PKA/CREB signaling pathway, which was essential for its pro-osteogenic effects.

Conclusions:

  • Psoralen is a potent synergistic enhancer of direct chemical reprogramming for generating functional osteoblast-like cells.
  • Psr-derived ciOBs exhibit robust bone-regenerative capacity in vivo.
  • The mechanism involves the activation of the ADCY9/cAMP/PKA/CREB pathway.