Programmable somitic-oscillator gene circuits for autonomous phase-specific delivery of regenerative morphogens
July 3
Progenitor populations exploit the segmentation oscillator to coordinate rhythmic waves of morphogenetic activity that influence both tissue homeostasis and degeneration, exemplified by cartilage erosion in chronic arthropathies. In these disorders, catabolic cues rise sharply at defined oscillator phases, coinciding with peak joint stiffness.
Phase-adaptive morphogen therapy seeks to release reparative signals at optimal moments to enhance efficacy, yet oscillator-guided regimens remain largely unexplored for living implants. Here, we engineered self-regulating somitic-oscillator gene circuits capable of synthesizing the chondrogenic antagonist Noggin with user-defined phase and amplitude.
We compared Noggin production from circuits harboring distinct segmentation promoter modules—Hairy1 E-boxes, Lfng D-boxes, or Hes7 response elements—and evaluated their performance under catabolic challenge in murine pre-differentiated induced pluripotent mesenchyme or cartilage organoids. Each construct exhibited a reproducible peak at a unique oscillator phase over successive cycles.
Engineered tissues secreted physiologically relevant quantities of Noggin on a rhythmic basis, preserving oscillator coherence and shielding extracellular matrix from degradative insult. The amplitude of Noggin release could be tuned by promoter selection without compromising phase fidelity.
These programmable somitic-oscillator circuits provide a framework for aligning implantable tissues with an individual’s intrinsic developmental rhythms, enabling optimized, self-regulated delivery of regenerative morphogens for targeted cartilage repair and beyond.