The role of muscle stem cells and fibro-adipogenic progenitors in female pelvic floor muscle regeneration following birth injury

Pelvic floor muscle (PFM) injury during childbirth is a key risk factor for subsequent pelvic floor disorders that affect millions of women worldwide. Muscle stem cells (MuSCs) play a central role in the regeneration of injured skeletal muscles, where they activate, proliferate, and differentiate to assure myogenesis needed for muscle recovery. For robust regenerative function, MuSCs require the support of fibro-adipogenic progenitors (FAPs) and immune cells. To elucidate the role of MuSCs, FAPs, and immune infiltrate in female PFM regeneration, we used radiation to perturb the system and followed PFM recovery in a simulated birth injury (SBI) rat model. Non-irradiated and irradiated rats were euthanized at 3,7, 10, and 28 days after SBI; PFMs were harvested and prepared for immunohistochemistry. Cross sectional area (CSA) of all PFM myofibers 28 days after injury in irradiated animals was significantly lower relative to non-irradiated injured controls, indicating impairment of PFM recovery. Following SBI in non-irradiated animals, the number of MuSCs and FAPs expanded significantly at 7 and 3 days after injury, respectively; this expansion did not occur in irradiated animals at the same time points. CSA of embryonic myosin heavy chain (eMyHC, marker of newly regenerated myofibers) positive fibers was also significantly smaller following SBI in irradiated muscles compared to PFMs from non-irradiated injured controls at 7 days. Our results demonstrate that loss of function and decreased expansion of MuSCs and FAPs associated with irradiation results in impaired PFM recovery, signifying essential roles for MuSCs and FAPs in the regenerative process of female PFMs after birth injury. These findings can inform the identification of novel preventative and therapeutic targets and the development of new treatments for PFM dysfunction and associated pelvic floor disorders.

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Pro-regenerative Extracellular Matrix Hydrogel Prevents and Mitigates Pathological Alterations of Pelvic Muscles Following Birth Injury

10.1101/2021.05.28.446170 ◽

2021 ◽

Author(s):

Pamela Duran ◽

Francesca Boscolo Sesillo ◽

Lindsey Burnett ◽

Shawn A Menefee ◽

Mark Cook ◽

...

Keyword(s):

Extracellular Matrix ◽

Pelvic Organ Prolapse ◽

Pelvic Floor ◽

Pelvic Floor Disorders ◽

Pelvic Floor Muscle ◽

Pelvic Organ ◽

Health Concern ◽

Birth Injury ◽

Post Injury ◽

Ecm Remodeling

Pelvic floor disorders, which include pelvic organ prolapse, and urinary and fecal incontinence, affect millions of women globally and represent a major public health concern. Pelvic floor muscle (PFM) dysfunction has been identified as one of the leading risk factors for the development of these morbid conditions. Even though childbirth, specifically vaginal delivery, has been long recognized as the most important potentially modifiable risk factor for PFM injury, the precise mechanisms of PFM dysfunction following childbirth remain elusive. In this study we demonstrate that PFMs undergo atrophy and severe fibrosis in parous women with symptomatic pelvic organ prolapse compared to age-matched nulliparous cadaveric donors without history of pelvic floor disorders. These pathological alterations are recapitulated in the pre-clinical rat model of simulated birth injury. The transcriptional signature of PFMs post-injury demonstrates a sustained inflammatory response, impairment in muscle anabolism, and persistent expression of extracellular matrix (ECM) remodeling genes. Next, we evaluated the administration of acellular injectable skeletal muscle extracellular matrix hydrogel for the prevention and mitigation of these pathological alterations. Treatment of PFMs with the biomaterial either at the time of birth injury or 4 weeks post-injury reduced muscle atrophy and mitigated fibrotic degeneration. By evaluating gene expression, we demonstrate that these changes are mainly driven by the hydrogel-induced modulation of the immune response and intramuscular fibrosis, as well as enhancement of the endogenous myogenesis. This work furthers our understanding of PFM birth injury and demonstrates proof-of-concept for a new pragmatic pro-regenerative biomaterial approach for treating injured PFMs.

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Cardiac regeneration: epicardial mediated repair

Proceedings of The Royal Society B Biological Sciences ◽

10.1098/rspb.2015.2147 ◽

2015 ◽

Vol 282 (1821) ◽

pp. 20152147 ◽

Cited By ~ 17

Author(s):

Teresa Kennedy-Lydon ◽

Nadia Rosenthal

Keyword(s):

Stem Cells ◽

Endothelial Cells ◽

Cardiac Fibroblasts ◽

Cardiac Regeneration ◽

Repair Process ◽

Regenerative Process ◽

Cardiac Stem Cell ◽

Cardiomyocyte Proliferation ◽

Lower Vertebrates

The hearts of lower vertebrates such as fish and salamanders display scarless regeneration following injury, although this feature is lost in adult mammals. The remarkable capacity of the neonatal mammalian heart to regenerate suggests that the underlying machinery required for the regenerative process is evolutionarily retained. Recent studies highlight the epicardial covering of the heart as an important source of the signalling factors required for the repair process. The developing epicardium is also a major source of cardiac fibroblasts, smooth muscle, endothelial cells and stem cells. Here, we examine animal models that are capable of scarless regeneration, the role of the epicardium as a source of cells, signalling mechanisms implicated in the regenerative process and how these mechanisms influence cardiomyocyte proliferation. We also discuss recent advances in cardiac stem cell research and potential therapeutic targets arising from these studies.

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