Kuo, C. K. | bioRxiv Science

bioRxiv2025

Tenotomized Achilles tendons of MRL/MpJ mice show scar-mediated healing, but have superior recovery of biomechanical properties

Tendon healing in Murphy Ross Large (MRL/MpJ) mice was examined using an Achilles tendon tenotomy model, a full transection model, compared to a patella focal injury model in which tendons in MRL/MpJ mice showed regenerative healing. After complete transection, the Achilles tendons of MRL/MpJ mice healed via scar formation, regardless of sex, as did C57BL/6J mice. Tensile testing found that mechanical properties of injured tendons of both MRL/MpJ female and male mice exhibited comparable levels to those of C57BL/6J female and male mice, respectively after 4 weeks of healing, which is during the remodeling phase. After 10 weeks of healing, injured tendons of MRL/MpJ mice possessed smaller heterotopic ossification volumes than those of C57BL/6J mice. Proteomics analysis revealed similar alterations to signaling pathways in injured tendons of MRL/MpJ and C57BL/6J male mice after 4 weeks of healing. However, among the altered pathways, actin cytoskeleton and integrin signaling pathways were two of the top pathways that were more prominently activated in C57BL/6J males than in MRL/MpJ males. These findings indicate that MRL/MpJ mice possess limited capacity to regenerate injured tendons after complete rupture, and that tenotomized Achilles tendons of MRL/MpJ male mice have lesser induction of heterotopic ossification and lower activation of the signaling pathways also induced with injury in C57BL/6J male mice.

pathology↗

bioRxiv2021

iPSC modeling shows uncompensated mitochondrial mediated oxidative stress underlies early heart failure in hypoplastic left heart syndrome

Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect with 30% mortality from heart failure (HF) in the first year of life, but why only some patients suffer early-HF and its cause remain unknown. Modeling using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) showed early-HF patient iPSC-CM have increased apoptosis, redox stress, and failed antioxidant response. This was associated with mitochondrial permeability transition pore (mPTP) opening, mitochondrial hyperfusion and respiration defects. Whereas iPSC-CM from patients without early-HF had hyper-elevated antioxidant response with increased mitochondrial fission and mitophagy. Single cell transcriptomics showed dichotomization by HF outcome, with mitochondrial dysfunction and endoplasmic reticulum (ER) stress associated with early-HF. Importantly, oxidative stress and apoptosis associated with early HF were rescued by sildenafil inhibition of mPTP opening or TUDCA suppression of ER stress. Together these findings demonstrate a new paradigm for modeling clinical outcome in iPSC-CM, demonstrating uncompensated mitochondrial oxidative stress underlies early HF in HLHS.

cell biology↗