Prx1⁺ MPCs Accumulate in the Dura Mater of Wild‐Type and p21^−/− Mice Followed by a Specific Reduction in p21^−/− Dural MPCs

Abstract

during revision surgeries for patients with epidural fibrosis. [2] Patients who experience incidental durotomies suffer from worse post-operative clinical results, such as a higher rate of reoperations, increased back pain, and reduced working ability. [3] However, appropriate treatment can diminish long-term sequelae post-dural injury. The use of synthetic and biological grafts to treat insults to the dura mater began in the 20th century, including polymer sheets, autografts, allografts, and even xenografts. [4] To date however, a successful graft which mimics perfectly the collagen fiber arrangement and accordingly the biomechanical properties of the dura mater remains elusive.Given loss of epidural fat can promote fibrosis in the vertebral environment, efforts have been made to re-introduce epidural fat into the vertebral column including engineered fat from adiposederived mesenchymal progenitor cells (MPCs), [1] injectable extracellular matrices, [5][6][7] and fat grafting. [6,[8][9][10] Attempts at preventing epidural fibrosis thus protecting the dura mater have also been made using biomaterials like DuraGen, [11] and injection of nonsteroidal anti-inflammatory drugs to re-balance the microenvironment to promote healing. [12] Regardless of the multiple different techniques being explored, no treatment exists that has gained wide clinical acceptance to prevent epidural fibrosis. Epidural fat contains a population of mesenchymal progenitor cells (MPCs), and this study explores the behavior of these cells on the adjacent dura mater during growth and in response toinjury in a p21 knockout mouse model. p21 −/− mice are known to have increased cell proliferation and enhanced tissue regeneration post-injury. Therefore, it is hypothesized that the process by which epidural fat MPCs maintain the dura mater can be accelerated in p21 −/− mice. Using a Prx1 lineage tracing mouse model, the epidural fat MPCs are found to increase in the dura mater over time in both C57BL/6 (p21 +/+ ) and p21 −/− mice; however, by 3 weeks post-tamoxifen induction, few MPCs are observed in p21 −/− mice. These endogenous MPCs also localize to dural injuries in both mouse strains, with MPCs in p21 −/− mice demonstrating increased proliferation. When epidural fat MPCs derived from p21 −/− mice are transplanted into dural injuries in C57BL/6 mice, these MPCs are found in the injury site. It is demonstrated that epidural fat MPCs play a role in dural tissue maintenance and are able to directly contribute to dural injury repair. This suggests that these MPCs have the potential to treat injuries and/or pathologies in tissues surrounding the spinal cord.