Obligatory role of Schwann cell‐specific erythropoietin receptors in erythropoietin‐induced functional recovery and neurogenic muscle atrophy after nerve injury

Talukder, Milton; Lee, Jung Il; Hegarty, John P.; Gurjar, Anagha; OʼBrien, Mary Elizabeth; Karuman, Zara; Wandling, Grant D.; Govindappa, Prem Kumar; Elfar, John C.

doi:10.1002/mus.27121

Cited by 9 publications

(6 citation statements)

References 26 publications

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“…In conclusion, we found EPO ameliorated the progression of post-TPNI with effects on nerve function, as well as macrophage phagocytosis. While our work and that of others may shed light on the role EPO plays in improving functional recovery in the traumatized limb [10,[47][48][49][50][51], this work outlines experiments that show effects on macrophage function in parallel with those functional findings. EPO likely improves nerve function after nerve injury via M2 phenotype macrophage phagocytosis of SCs debris with early anti-apoptotic and anti-inflammatory effects.…”

Section: Discussionmentioning

confidence: 78%

Erythropoietin M2 macrophage Signaling Promotes Schwann Cells Clearance and Functional Recovery Following Peripheral Nerve Injury

Govindappa

Elfar

2022

The FASEB Journal

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Background Traumatic peripheral nerve injury (TPNI) obliterates axons and Schwann cells (SCs) that must be cleared through phagocytosis to allow surviving SCs to de‐differentiate and divide and guide the regeneration process. In TPNI, macrophage (MØ) infiltration and early phenotypic transitions (M1 to M2) are critical for the phagocytosis of SCs debris. Delayed phagocytosis critically aggravates inflammation and impairs MØ function, which leads to failure to advance SC orchestration and neuronal regeneration. Erythropoietin (EPO), a pluripotent hormone, helps to guide MØs and SC transition post‐TPNI. The significance of the effects of EPO on debris clearance, apoptosis, myelination, and functional improvement is unknown, despite much effort motivating clinical translation of EPO for TPNI. We hypothesized that a role in supporting M2 phenotype macrophages after TPNI might explain EPO’s neuroprotective function through SCs debris clearance. Methods and Results We evaluated EPO’s effect on sciatic nerve crush injury (SNCI) and found EPO treatment (5000 IU/kg, intraperitoneally, post‐surgery days 1, 2, and 3,) increased myelination and sciatic functional index (SFI) and augmented anti‐apoptosis and phagocytosis of myelin debris via CD206+ macrophages when compared to saline treatment in the mouse. EPO increased efferocytosis of apoptotic sciatic nerve derived Schwann cells (SNSCs) both in bone marrow derived macrophages (BMMØs) and peritoneal derived macrophages (PMØs) in‐vitro, as well as in PMØs in‐vivo by immunofluorescence (IF) and flow cytometry. EPO treatment significantly attenuated BMMØ pro‐inflammatory genes (IL1b, iNOS, and CD68) and augmented anti‐inflammatory genes (IL10, and CD163) in addition to the cell surface marker CD206 expression after lipopolysaccharide (LPS) induction. EPO also showed anti‐apoptotic (Annexin V/ 7AAD) effects in BMMØs. Our data demonstrate that EPO promotes the M2 phenotype macrophages to ameliorate SN apoptosis and efferocytosis of dying SCs and myelin debris and improves SN functional recovery following SNCI. Conclusions To the best of our knowledge, this is the first study to demonstrate EPO’s ameliorative effect on the progression of post‐TPNI via M2 phenotype macrophage phagocytosis of SCs debris with early anti‐apoptotic and anti‐inflammatory effects. These data may support the findings of other researchers and might shed light on the role of EPO in improving functional recovery in the traumatized limb.

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Section: Discussionmentioning

confidence: 78%

Erythropoietin M2 macrophage Signaling Promotes Schwann Cells Clearance and Functional Recovery Following Peripheral Nerve Injury

Govindappa

Elfar

2022

The FASEB Journal

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“…We have established Schwann cell specific Mpz-EPOR-KO mice using a multi-step breeding process of EPOR flox/flox homozygous and MpzCre hemizygous mice [ 18 ]. Briefly, loxP-flanked exons 1–4 of the EPOR genomic sequence were ablated in Schwann cells using the Cre-loxP system, and deletion of EPOR was verified by genotyping of genomic EPOR alleles in VN (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The specific knockout of EPOR in Schwann cells (MpzCre-EPOR flox/flox , synonym with Mpz-EPOR-KO) was generated by cross-mating floxed EPOR (EPOR flox/flox ) mice with myelin protein zero (Mpz) promoter-driven Cre recombinase (MpzCre) mice from Jackson Laboratories as described in our publication [ 18 ]. EPOR deletion was confirmed using polymerase chain reaction (PCR) with genomic DNA from the tail, intestine segments (duodenum, jejunum, and ileum), vagus nerve, and vagus nerve derived Schwann cells (VNSC).…”

Section: Methodsmentioning

confidence: 99%

“…To assess EPOR gene expression, the vagus nerve of the MpzCre-EPOR flox/flox and EPOR flox/flox (control) mice were harvested and the total RNA was extracted using miRNeasy mini kit (#217,004; Qiagen) [ 18 ]. Next, RNA was reverse transcribed to cDNA (#1,708,840; Bio-Rad), and the relative mRNA expression of the EPOR (normalized to GAPDH) was quantified using Fast SYBR Green Master Mix (#4,385,612; Applied Biosystems).…”

Section: Methodsmentioning

confidence: 99%

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A critical role for erythropoietin on vagus nerve Schwann cells in intestinal motility

et al. 2023

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Background Dysmotility and postoperative ileus (POI) are frequent major clinical problems post-abdominal surgery. Erythropoietin (EPO) is a multifunctional tissue-protective cytokine that promotes recovery of the intestine in various injury models. While EPO receptors (EPOR) are present in vagal Schwann cells, the role of EPOR in POI recovery is unknown because of the lack of EPOR antagonists or Schwann-cell specific EPOR knockout animals. This study was designed to explore the effect of EPO via EPOR in vagal nerve Schwann cells in a mouse model of POI. Results The structural features of EPOR and its activation by EPO-mediated dimerization were understood using structural analysis. Later, using the Cre-loxP system, we developed a myelin protein zero (Mpz) promoter-driven knockout mouse model of Schwann cell EPOR (MpzCre-EPORflox/flox / Mpz-EPOR-KO) confirmed using PCR and qRT-PCR techniques. We then measured the intestinal transit time (ITT) at baseline and after induction of POI with and without EPO treatment. Although we have previously shown that EPO accelerates functional recovery in POI in wild type mice, EPO treatment did not improve functional recovery of ITT in POI of Mpz-EPOR-KO mice. Conclusions To the best of our knowledge, this is the first pre-clinical study to demonstrate a novel mouse model of EPOR specific knock out on Schwan cells with an effect in the gut. We also showed novel beneficial effects of EPO through vagus nerve Schwann cell-EPOR in intestinal dysmotility. Our findings suggest that EPO-EPOR signaling in the vagus nerve after POI is important for the functional recovery of ITT.

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“…Angiogenesis is one of the most crucial initial processes after nerve injury, playing an essential role in axonal sprouting, regeneration, and reinnervation [ 28 , 29 ]. Macroscopically, the microvessel density was significantly higher in the EPO-PLGA-PEG group which indicated an optimal regenerated condition for tissue recovery (Fig.…”

Section: Resultsmentioning

confidence: 99%

Erythropoietin-PLGA-PEG as a local treatment to promote functional recovery and neurovascular regeneration after peripheral nerve injury

et al. 2022

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Background Traumatic peripheral nerve injury (TPNI) is a major medical problem with no universally accepted pharmacologic treatment. We hypothesized that encapsulation of pro-angiogenic erythropoietin (EPO) in amphiphilic PLGA-PEG block copolymers could serve as a local controlled-release drug delivery system to enhance neurovascular regeneration after nerve injury. Methods In this study, we synthesized an EPO-PLGA-PEG block copolymer formulation. We characterized its physiochemical and release properties and examined its effects on functional recovery, neural regeneration, and blood vessel formation after sciatic nerve crush injury in mice. Results EPO-PLGA-PEG underwent solution-to-gel transition within the physiologically relevant temperature window and released stable EPO for up to 18 days. EPO-PLGA-PEG significantly enhanced sciatic function index (SFI), grip strength, and withdrawal reflex post-sciatic nerve crush injury. Furthermore, EPO-PLGA-PEG significantly increased blood vessel density, number of junctions, and myelinated nerve fibers after injury. Conclusion This study provides promising preclinical evidence for using EPO-PLGA-PEG as a local controlled-release treatment to enhance functional outcomes and neurovascular regeneration in TPNI.

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Obligatory role of Schwann cell‐specific erythropoietin receptors in erythropoietin‐induced functional recovery and neurogenic muscle atrophy after nerve injury

Cited by 9 publications

References 26 publications

Erythropoietin M2 macrophage Signaling Promotes Schwann Cells Clearance and Functional Recovery Following Peripheral Nerve Injury

Erythropoietin M2 macrophage Signaling Promotes Schwann Cells Clearance and Functional Recovery Following Peripheral Nerve Injury

A critical role for erythropoietin on vagus nerve Schwann cells in intestinal motility

Erythropoietin-PLGA-PEG as a local treatment to promote functional recovery and neurovascular regeneration after peripheral nerve injury

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