Adipose-Derived Stem Cells Alleviate Denervation-Induced Muscle Atrophy by Promoting M2 Macrophage Polarization and Reducing Inflammation.

Abstract

INTRODUCTION/AIMS: Denervation-induced muscle atrophy lacks effective therapies. Adipose-derived stem cells (ADSCs) show promise for tissue repair. This study aimed to evaluate the effect of local ADSC delivery on denervated muscle, investigate underlying mechanisms, and track ADSC distribution and migration in&#xa0;vivo. METHODS: In a mouse model of sciatic nerve transection and immediate reverse autograft repair, ADSCs or phosphate-buffered saline (PBS) were injected into the right gastrocnemius following nerve injury. Magnetic resonance imaging (MRI) and in&#xa0;vivo imaging system (IVIS) tracked ADSC migration. Muscle strength and gastrocnemius mass were measured. Histology (H&E, Masson), immunostaining (MyoD, CD163), and the real-time reverse transcription polymerase chain reaction (RT-PCR) assessed fiber size, fibrosis, muscle regeneration, M2 macrophage infiltration, and inflammatory gene expression. Endpoints were measured 1&#x2009;week after the final injection (4&#x2009;weeks post-injury). RESULTS: IVIS showed that injected ADSCs were visualized for 3-5&#x2009;days in&#xa0;vivo while MRI localized cells predominantly to the quadriceps and knee regions. ADSC treatment increased normalized muscle strength (p&#x2009;<&#x2009;0.05), normalized gastrocnemius muscle weight (p&#x2009;<&#x2009;0.001) and fiber diameter (p&#x2009;<&#x2009;0.05); downregulated MMP2 expression (p&#x2009;<&#x2009;0.001), enhanced MyoD+ cell count (p&#x2009;<&#x2009;0.001), and promoted M2 macrophage infiltration (CD163+ cells, p&#x2009;<&#x2009;0.05; ARG1 mRNA, p&#x2009;<&#x2009;0.05). RT-PCR revealed reduced pro-inflammatory transcripts (IL-6, IL-1b; p&#x2009;<&#x2009;0.05). DISCUSSION: ADSCs ameliorate denervation-induced muscle atrophy by improving muscle function and structure via M2 macrophage infiltration, MyoD upregulation, MMP2 inhibition, and reduced inflammation. These findings underscore the therapeutic potential of ADSCs for mitigating muscle atrophy following nerve injury, although the acute injury model used may not fully represent chronic clinical denervation.