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Erythropoietin Promotes Schwann Cell Repair, Phagocytosis, and Nerve Regeneration: Bulk RNA Sequencing of the Sciatic Nerve After a Crush injury
Prem Kumar Govindappa, PhD
1, Govindaraj Ellur, PhD
1, John P. Hegarty, PhD
2, Akash Gupta, PhD
1; John C Elfar, MD, FACS
1(1)The University of Arizona, Tucson, AZ, (2)The Pennsylvania State University, Hershey, PA
Introduction: Peripheral nerve crush injury (PNCI) damages Schwann cells (SCs), myelin, and axons, causing inflammation and cell death that hinder nerve regeneration and impair function. The transformation of surviving SCs to repair SCs (rSCs) and their coordination with macrophages (M?s) to clear debris through phagocytosis is crucial. We found that erythropoietin (EPO), an FDA-approved treatment for anemia, enhances post-PNCI functional recovery by increasing M? phagocytosis. However, the specific effects of EPO on SC-phagocytosis and the underlying reparative mechanisms remain unclear. We hypothesized EPO-enhanced debris clearance involves collaborative effects on resident SCs and incoming M?s, by reducing apoptosis, and improving myelination, ultimately leading enhanced functional recovery post-PNCI.
Materials and Methods:We used 10-week-old male C57BL/6J mice (25 ± 3 g) for an IACUC-approved sciatic nerve crush injury (SNCI), applying 4.2 MPa of pressure for 30 seconds. Mice (n = 4 to 6 per group) were randomly assigned to sham, SNCI (saline), and SNCI + EPO (5000 IU/kg, given intraperitoneally immediately and 24- and 48-hours post-SNCI). The sciatic functional index (SFI) was assessed on days 3, 5, and 7, followed by an assessment of bulk RNA sequencing and validation of SC myelin phagocytosis, apoptosis, proliferation, and repair status.
In-vitro studies of SC assessed myelin phagocytosis, dead SCs, and reparative function under lipopolysaccharide (LPS)-stress. Results are presented as the mean ± SEM, and a P-value of less than 0.05 was considered statistically significant.
Results:Nerve tissue RNA sequencing demonstrated that EPO significantly influenced several biological pathways and associated genes, particularly those related to apoptosis, differentiation, proliferation, phagocytosis, myelination, and neurogenesis on days 3, 5, and 7 post-SNCI. Validation studies confirmed that EPO reduced apoptosis (TUNEL), enhanced SC repair (c-Jun and p75-NTR), increased proliferation (Ki67), and promoted phagocytosis of myelin debris by rSCs and M?s at the nerve injury at those same time points post-SNCI. These improvements supported enhanced walking function (SFI).
In-vitro studies showed that EPO enhanced SC early de-differentiation (high c-Jun and p75-NTR) and subsequent re-differentiation (high EGR2 and low c-Jun and p75-NTR) under LPS stress at 24 and 72 hours. EPO also significantly increased the proliferation of rSCs and the phagocytosis of myelin and dead SCs under LPS stress conditions.
Conclusions:Post-PNCI EPO supports transcriptomic changes that explain functional improvement including enhanced rSC and M? abilities to clear debris and promote nerve regeneration. This is a rationale for EPO in treating nerve trauma.
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