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

Francesca Boscolo Sesillo; Varsha Rajesh; Michelle Wong; Pamela Duran; John B Rudell; Courtney P Rundio; Brittni B Baynes; Louise C Laurent; Alessandra Sacco; Karen L Christman; Marianna Alperin

doi:10.1038/s41536-022-00264-1

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

NPJ Regen Med. 2022 Dec 16;7(1):72. doi: 10.1038/s41536-022-00264-1.

Authors

Francesca Boscolo Sesillo^{1

2}, Varsha Rajesh³, Michelle Wong¹, Pamela Duran^{2

4}, John B Rudell^{1

2}, Courtney P Rundio^{1

2}, Brittni B Baynes¹, Louise C Laurent^{2

5}, Alessandra Sacco⁶, Karen L Christman^{2

4}, Marianna Alperin^{7

8}

Affiliations

¹ Department of Obstetrics, Gynecology, and Reproductive Sciences, Division of Female Pelvic Medicine and Reconstructive Surgery, University of California, San Diego, San Diego, CA, 92037, USA.
² Sanford Consortium for Regenerative Medicine, La Jolla, CA, 92037, USA.
³ Division of Biological Sciences, University of California, San Diego, La Jolla, CA, 92161, USA.
⁴ Department of Bioengineering, University of California, San Diego, La Jolla, CA, 92093, USA.
⁵ Department of Obstetrics, Gynecology, and Reproductive Sciences, Division of Maternal-Fetal Medicine, University of San Diego, La Jolla, CA, 92037, USA.
⁶ Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.
⁷ Department of Obstetrics, Gynecology, and Reproductive Sciences, Division of Female Pelvic Medicine and Reconstructive Surgery, University of California, San Diego, San Diego, CA, 92037, USA. malperin@health.ucsd.edu.
⁸ Sanford Consortium for Regenerative Medicine, La Jolla, CA, 92037, USA. malperin@health.ucsd.edu.

Abstract

Pelvic floor muscle (PFM) injury during childbirth is a key risk factor for pelvic floor disorders that affect millions of women worldwide. Muscle stem cells (MuSCs), supported by the fibro-adipogenic progenitors (FAPs) and immune cells, are indispensable for the regeneration of injured appendicular skeletal muscles. However, almost nothing is known about their role in PFM regeneration following birth injury. To elucidate the role of MuSCs, FAPs, and immune infiltrate in this context, we used radiation to perturb cell function and followed PFM recovery in a validated simulated birth injury (SBI) rat model. Non-irradiated and irradiated rats were euthanized at 3,7,10, and 28 days post-SBI (dpi). Twenty-eight dpi, PFM fiber cross-sectional area (CSA) was significantly lower and the extracellular space occupied by immune infiltrate was larger in irradiated relative to nonirradiated injured animals. Following SBI in non-irradiated animals, MuSCs and FAPs expanded significantly at 7 and 3 dpi, respectively; this expansion did not occur in irradiated animals at the same time points. At 7 and 10 dpi, we observed persistent immune response in PFMs subjected to irradiation compared to non-irradiated injured PFMs. CSA of newly regenerated fibers was also significantly smaller following SBI in irradiated compared to non-irradiated injured PFMs. Our results demonstrate that the loss of function and decreased expansion of MuSCs and FAPs after birth injury lead to impaired PFM recovery. These findings form the basis for further studies focused on the identification of novel therapeutic targets to counteract postpartum PFM dysfunction and the associated pelvic floor disorders.

Abstract

Grants and funding