Effects of Trauma Plasma-Derived Exosomes on Hematopoietic Progenitor Cells

Munley, Jennifer A.; Kelly, Lauren; Gillies, Gwendolyn S; Kannan, Kolenkode B.; Pons, Erick E; Bible, Letitia; Efron, Philip A.; Mohr, Alicia M.

doi:10.1097/shk.0000000000002094

Cited by 4 publications

(27 citation statements)

References 30 publications

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“…Another important limitation is that we did not obtain postinoculation bacterial counts or lung histology on day 7. However our previous study validating the polytrauma plus pneumonia model included lethal dose testing in Sprague-Dawley rats to confirm appropriate Pseudomonas dosage to induce a clinically significant pneumonia 23 . This study also included lung histology assessment on day 2 demonstrating histologic changes of pneumonia 23 .…”

Section: Discussionmentioning

confidence: 99%

“…However our previous study validating the polytrauma plus pneumonia model included lethal dose testing in Sprague-Dawley rats to confirm appropriate Pseudomonas dosage to induce a clinically significant pneumonia 23 . This study also included lung histology assessment on day 2 demonstrating histologic changes of pneumonia 23 . This study did not assess suppression of nonerythroid bone marrow cell lines, which would likely have clinical significance because impaired clearance of secondary infections in the setting of leukopenia may affect recovery from anemia.…”

Section: Discussionmentioning

confidence: 99%

“…Rodent surgery was performed as previously described 23 . Briefly, after induction of anesthesia with isoflurane (Patterson Veterinary), 1 mg/kg sustained-release buprenorphine (ZooPharm, Laramie, WY) was administered subcutaneously.…”

Section: Methodsmentioning

confidence: 99%

“…Bone marrow cellularity and viability were assessed using 0.4% Trypan blue staining on a TC20 automated cell counter (Bio-Rad, Hercules, CA). Bone marrow erythroid progenitor colony growth assays were performed for colony-forming units—granulocyte, erythrocyte, monocyte, megakaryocyte (CFU-GEMM); BFU-E; and CFU-E as in prior works 14,23 . Briefly, 5 × 10 4 cells (1 mL) were plated in duplicate and incubated at 37°C in 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

“…20 Burn injury has been shown to impede the late maturation of orthochromatic erythroblasts into reticulocytes by restricting the enucleation step. 22 Using our previously validated preclinical model of multicompartmental trauma and postinjury pneumonia, 23,24 this study sought to determine the impact of infection following injury on bone marrow function and erythropoiesis. Since macrophages are pivotal in response to infection, we hypothesized that bone marrow dysfunction, defective terminal erythropoiesis, and anemia would be exacerbated in the setting of postinjury infection.…”

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confidence: 99%

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Posttraumatic pneumonia exacerbates bone marrow erythropoietic dysfunction

Gillies,

Munley,

Kelly

et al. 2023

J Trauma Acute Care Surg

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Introduction Pneumonia is a common complication after severe trauma that is associated with worse outcomes with increased mortality. Critically ill trauma patients also have persistent inflammation and bone marrow dysfunction that manifests as persistent anemia. Terminal erythropoiesis, which occurs in bone marrow structures called erythroblastic islands (EBIs), has been shown to be impacted by trauma. Using a preclinical model of polytrauma and pneumonia, we sought to determine the effect of infection on bone marrow dysfunction and terminal erythropoiesis. Methods Male and female Sprague-Dawley rats aged 9-11 weeks were subjected to either polytrauma (PT) (lung contusion, hemorrhagic shock, cecectomy, and bifemoral pseudofracture) or PT with postinjury day 1 Pseudomonas pneumonia (PT + PNA) and compared to a naïve cohort. EBIs were isolated from bone marrow samples and imaged via confocal microscopy. Hemoglobin, early bone marrow erythroid progenitors, erythroid cells/EBI, and % reticulocytes/EBI were measured on day 7. Significance was defined as *p < 0.05. Results Day seven hemoglobin was significantly lower in both PT and PT + PNA groups compared to naïve (10.8±0.6* and 10.9±0.7* vs. 12.1±0.7 g/dL). Growth of bone marrow early erythroid progenitors (CFU-GEMM, BFU-E, and CFU-E) seven was significantly reduced in PT + PNA compared to both PT and naïve. Despite a peripheral reticulocytosis following PT and PT + PNA, the percentage of reticulocytes/EBI was not different between naïve, PT and PT + PNA. However, the number of erythroblasts/EBI was significantly lower in PT + PNA compared to PT and naïve (2.9±1.5* vs. 8.9±1.1 cells/EBI macrophage). In addition to changes in EBI composition, EBIs were also found to have significant structural changes following PT and PT + PNA. Conclusions Multicompartmental PT altered late-stage erythropoiesis and these changes were augmented with the addition of pneumonia. To improve outcomes following trauma and pneumonia, we need to better understand how alterations in EBI structure and function impact persistent bone marrow dysfunction and anemia. Level of Evidence N/A

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Posttraumatic pneumonia exacerbates bone marrow erythropoietic dysfunction

Gillies,

Munley,

Kelly

et al. 2023

J Trauma Acute Care Surg

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Current updates in precision and personalized medicine in sepsis and trauma

Drury,

Wallet,

Maile

et al. 2024

Surgery

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Exosomal microRNA following severe trauma: Role in bone marrow dysfunction

Munley,

Willis,

Gillies

et al. 2023

J Trauma Acute Care Surg

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Introduction Severe trauma disrupts bone marrow function and is associated with persistent anemia and altered hematopoiesis. Previously, plasma-derived exosomes isolated after trauma have been shown to suppress in vitro bone marrow function. However, the cargo contained in these vesicles has not been examined. We hypothesized that trauma plasma-derived exosomes exhibit microRNA (miR) changes that impact bone marrow function after severe injury. Methods Plasma was collected from a prospective, cohort study of trauma patients (n = 15; 7 males, 8 females) with hip and/or femur fractures and an injury severity score (ISS) ≥ 15; elective total hip arthroplasty (THA) patients (n = 8; 4 males, 4 females) served as operative controls. Exosomes were isolated from plasma with the Invitrogen Total Exosome Isolation Kit and RNA was isolated using a miRNeasy Mini Kit. Direct quantification of miRNA was performed by NanoString Technologies on a human miRNA gene panel and analyzed with nSolver with significance defined as p < 0.05. Results There were no differences in age or sex distribution between trauma and THA groups; the average ISS was 23. Trauma plasma-derived exosomes had 60 miR identities that were significantly downregulated and 3 miR upregulated when compared to THA (p < 0.05). Twelve of the downregulated miR have a direct role in hematopoiesis regulation. Further, male trauma plasma-derived exosomes demonstrated downregulation of 150 miR compared to male THA (p < 0.05). Female trauma plasma-derived exosomes demonstrated downregulation of only four miR and upregulation of two miR compared to female THA (p < 0.05). Conclusions We observed downregulation of 12 miRNA linked to hematopoiesis along with sexual dimorphism in miR expression from plasma-derived exosomes following severe trauma. Understanding sexually dimorphic miR expression provides new insight into sex-based changes in postinjury systemic inflammation, immune system dysregulation, and bone marrow dysfunction and will aid us in more precise future potential therapeutic strategies. Level of Evidence II, Prognostic and Epidemiological

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Effects of Trauma Plasma-Derived Exosomes on Hematopoietic Progenitor Cells

Cited by 4 publications

References 30 publications

Posttraumatic pneumonia exacerbates bone marrow erythropoietic dysfunction

Posttraumatic pneumonia exacerbates bone marrow erythropoietic dysfunction

Current updates in precision and personalized medicine in sepsis and trauma

Exosomal microRNA following severe trauma: Role in bone marrow dysfunction

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