Correction: Paracrine Factors of Mesenchymal Stem Cells Recruit Macrophages and Endothelial Lineage Cells and Enhance Wound Healing.

[This corrects the article DOI: 10.1371/journal.pone.0001886.].

Prospective validation of the role of PET/CT in detecting disease after neoadjuvant chemotherapy in advanced ovarian cancer.

OBJECTIVES: The study aimed to compare the diagnostic accuracies of 2-[18F]FDG PET/CT and contrast-enhanced CT (ceCT) after neoadjuvant chemotherapy (NACT) in advanced ovarian cancer (OC). MATERIALS AND METHODS: This study consisted historical observational cohort and prospective validation cohort. Patients with newly diagnosed stage III-IV OC scheduled for NACT were recruited, with imaging performed after three to six cycles of NACT before interval debulking surgery. Nineteen regions in the abdominopelvic cavity were scored for the presence and absence of disease, referenced to the intra-operative findings or histological specimens. Diagnostic metrics were compared using McNemar's test. RESULTS: In the historical cohort (23 patients, age 58 ± 13), 2-[18F]FDG PET had an overall accuracy (Acc) 82%, sensitivity (Sen) 38%, specificity (Spe) 97%, positive predictive value (PPV) 79% and negative predictive value (NPV) 82%; ceCT had an overall Acc 86%, Sen 64%, Spe 93%, PPV 75% and NPV 89%. In the prospective cohort (46 patients, age 59 ± 9), 2-[18F] FDG PET had an overall Acc 87%, Sen 48%, Spe 98%, PPV 84% and NPV 88%; ceCT had an overall Acc 89%, Sen 66%, Spe 95%, PPV 77% and NPV 91%. No significant difference was demonstrated between the two imaging modalities (p > 0.05). High false-negative rates were observed in the right subdiaphragmatic space, omentum, bowel mesentery and serosa. High omental metabolic uptake after NACT was associated with histological non-responders (p < 0.05). CONCLUSION: 2-[18F]FDG PET/CT had no additional value over ceCT with comparable diagnostic accuracy in detecting disease after NACT in advanced OC. CLINICAL RELEVANCE STATEMENT: 2-[18F]FDG PET/CT is not superior to contrast-enhanced CT in determining disease after neoadjuvant chemotherapy in advanced ovarian cancer; contrast-enhanced CT should be suffice for surgical planning before interval debulking surgery. KEY POINTS: • Additional value of 2-[18F]FDG PET/CT over contrast-enhanced CT is undefined in detecting disease after neoadjuvant chemotherapy. • 2-[18F]FDG PET/CT has comparable diagnostic accuracy compared to contrast-enhanced CT. • Contrast-enhanced CT will be suffice for surgical planning after neoadjuvant chemotherapy.

Ivabradine in the Prevention, and Reduction in Size, of Perioperative Myocardial Injury in Patients Undergoing Orthopedic Surgery for Acute Fracture.

BACKGROUND: Perioperative myocardial injury is common after major noncardiac surgery and is associated with adverse outcomes. This study investigated the use of ivabradine in patients undergoing urgent surgery for fracture. METHODS AND RESULTS: This was a prospective, double-blind, placebo-controlled, randomized clinical trial. Participants were enrolled 1:1 into ivabradine or placebo arm, and study drug was commenced before operation and continued for 7 days or until discharge. High-sensitivity troponin I was measured daily using Abbott Alinity analyzer and assay, and heart rate data were obtained using continuous Holter monitoring. A total of 199 patients underwent acute orthopedic surgery, 98 in the ivabradine group and 101 in the placebo group. The mean age was 78.7 years (range, 77.5-79.9 years), with 68% women. The average heart rate was 5 to 11 beats per minute lower in the ivabradine group compared with the placebo group at all time points (P<0.001 for all). There was no statistically significant difference between the ivabradine and placebo groups in the number of patients who had perioperative myocardial injury: 28.6% versus 31.6% (P=0.71). In patients with perioperative myocardial injury, average peak troponin was 168.8 ng/L (±431.2 ng/L) in the ivabradine group and 2094.5 ng/L (±7201.9 ng/L) in the placebo group (P=0.16). There was no statistically significant difference between groups in 30-day mortality, blood pressure, stroke, or major adverse cardiovascular event. CONCLUSIONS: Starting ivabradine preoperatively in elderly patients requiring acute surgery for fracture did not result in a statistically significant difference in the incidence of perioperative myocardial injury. There was no statistically significant difference in morbidity, mortality, or adverse events between treatment groups. REGISTRATION: URL: https://www.anzctr.org.au/; Unique identifier: ACTRN12616001634460p.

Simultaneous Integrated Boost for Dose Escalation in Node-Positive Cervical Cancer: 5-Year Experience in a Single Institution.

This study retrospectively evaluates clinical outcomes of dose escalation to involved nodes using volumetric modulated arc therapy (VMAT) with simultaneous integrated boost (SIB) for node-positive locally advanced cervical cancer (LACC) at a single institution. Consecutive patients with node-positive LACC (FIGO2018 IIIC1-IVA) who received definitive chemoradiotherapy by VMAT 45 Gy in 25 fractions with SIB to 55-57.5 Gy, followed by magnetic resonance image-guided adaptive brachytherapy (IGABT) between 2018 and 2022 were identified. A standardized strategy regarding nodal boost delivery and elective para-aortic (PAO) irradiation was employed. Primary endpoints were involved nodal control (INC) and regional nodal control (RNC). Secondary endpoints were pelvic control (PC), locoregional control (LRC), disease-free survival (DFS), overall survival (OS), failure pattern, and radiotherapy-related toxicities. A total of 234 involved nodes (182 pelvic and 52 PAO) in 54 patients, with a median of 3 involved nodes per patient (range 1-16), were analyzed. After a median follow-up of 19.6 months, excellent INC was achieved, with four (2%) boost-volume failures occurring in three patients. The 2-year actuarial RNC, PC, LRC, DFS, and OS were 93%, 87%, 87%, 78%, and 85%, respectively. Adenocarcinoma histology was associated with worse RNC (p = 0.02) and OS (p = 0.04), whereas the primary tumor maximum standardized uptake value (SUVmax) was associated with worse PC (p = 0.04) and LRC (p = 0.046) on univariate analysis. The incidence of grade ≥3 acute and late radiotherapy-related toxicity were 2% and 4%, respectively. Treatment of node-positive LACC with VMAT with SIB allows safe and effective dose escalation. The 5-year local experience demonstrated excellent treatment outcomes without additional toxicity.

Geometric and dosimetric consequences of intra-fractional movement in single isocenter non-coplanar stereotactic radiosurgery.

PURPOSE: To investigate the geometric and dosimetric impacts of intra-fractional movement for patients with single or multiple brain metastasis treated using Varian Hyperarc™ mono-isocentric radiosurgery. METHODS: A total of 50 single or hypo-fractionated Hyperarc™ treatment courses (118 lesions) were included in the analysis. Intra-fractional translational and rotational movements were quantified according to the post-treatment cone-beam CT (CBCT). Geometric displacements of all targets were calculated individually based on the assessed head movement in each treatment fraction and their relationships with treatment time and target-to-isocenter distances were studied. For dosimetric analysis, only single-fraction treatments (56 lesions) were included. Re-planning was performed with 0, 1, and 2 mm planning target volume (PTV) margins. Doses were then re-calculated on rotated CT images with isocenter shifted which emulate the change in patient treatment position. Target coverage, target and normal brain doses before and after intra-fractional movement were compared. RESULTS: The mean 3D target displacements was 0.6 ± 0.3 (SD) mm. Target shifts for patients treated within 10 min were significantly smaller than those treated in longer sessions. No correlation was found between target shift and target-to-isocenter distance as the origin of head rotation was not located at the isocenter. Loss of target coverage and minimum Gross Tumor Volume (GTV) dose due to intra-fractional movement were apparent only when no margin was used, leading to an extra 23% of the targets violating the dose acceptance criteria, in contrast, the effects on normal brain V12Gy were negligible regardless of the margin used. The use of 1 mm PTV margin can compensate clinically significant geographical miss caused by intra-fractional movements while limiting V12Gy to within dose criteria for 88% of the cases. The plan acceptance rate (fulfillment of both target and normal brain dose criteria) after intra-fractional movement was also the highest with the 1 mm margin. CONCLUSION: Although intra-fractional movements during Hyperarc™ treatments were small, there were substantial dosimetric effects due to the sharp dose fall-off near target boundaries. These effects could be mitigated by using a 1 mm PTV margin and maintaining the effective treatment time to within 10 min.

Online health communities and the patient-doctor relationship: An institutional logics perspective.

Taking an institutional logics perspective, this study investigates how "internet-informed" patients manage tensions between the logic of personal choice and the logic of medical professionalism as they navigate treatment decisions and the patient-doctor relationship. Based on 44 semi-structured interviews with members of an online health community for people with diabetes, this study finds that patients exercise a great deal of agency in evaluating healthcare options not only by activating the logic of personal choice but also by appropriating the logic of medical professionalism. Furthermore, patients are strategic in deciding what community advice to share with their doctor or nurse depending on the healthcare professionals' reaction to the logic of personal choice. In contrast to many previous studies that emphasise patient consumerism fuelled by information on the Internet, this study provides a more nuanced picture of patient-doctor relationship engendered by patients' participation in online health communities.

Multi-shot Diffusion-Weighted MRI With Multiplexed Sensitivity Encoding (MUSE) in the Assessment of Active Inflammation in Crohn's Disease.

BACKGROUND: Single-shot diffusion-weighted imaging (ssDWI) has been shown useful for detecting active bowel inflammation in Crohn's disease (CD) without MRI contrast. However, ssDWI suffers from geometric distortion and low spatial resolution. PURPOSE: To compare conventional ssDWI with higher-resolution ssDWI (HR-ssDWI) and multi-shot DWI based on multiplexed sensitivity encoding (MUSE-DWI) for evaluating bowel inflammation in CD, using contrast-enhanced MR imaging (CE-MRI) as the reference standard. STUDY TYPE: Prospective. SUBJECTS: Eighty nine patients with histological diagnosis of CD from previous endoscopy (55 male/34 female, age: 17-69 years). FIELD STRENGTH/SEQUENCES: ssDWI (2.7 mm × 2.7 mm), HR-ssDWI (1.8 mm × 1.8 mm), MUSE-DWI (1.8 mm × 1.8 mm) based on echo-planar imaging, T2-weighted imaging, and CE-MRI sequences, all at 1.5 T. ASSESSMENT: Five raters independently evaluated the tissue texture conspicuity, geometry accuracy, minimization of artifacts, diagnostic confidence, and overall image quality using 5-point Likert scales. The diagnostic performance (sensitivity, specificity and accuracy) of each DWI sequences was assessed on per-bowel-segment basis. STATISTICAL TESTS: Inter-rater agreement for qualitative evaluation of each parameter was measured by the intra-class correlation coefficient (ICC). Paired Wilcoxon signed-rank tests were performed to evaluate the statistical significance of differences in qualitative scoring between DWI sequences. A P value <0.05 was considered to be statistically significant. RESULTS: Tissue texture conspicuity, geometric distortions, and overall image quality were significantly better for MUSE-DWI than for ssDWI and HR-ssDWI with good agreement among five raters (ICC: 0.70-0.89). HR-ssDWI showed significantly poorer performance to ssDWI and MUSE-DWI for all qualitative scores and had the worst diagnostic performance (sensitivity of 57.0% and accuracy of 87.3%, with 36 undiagnosable cases due to severe artifacts). MUSE-DWI showed significantly higher sensitivity (97.5% vs. 86.1%) and accuracy (98.9% vs. 95.1%) than ssDWI for detecting bowel inflammation. DATA CONCLUSION: MUSE-DWI was advantageous in assessing bowel inflammation in CD, resulting in improved spatial resolution and image quality. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 2.

P2RY8 variants in lupus patients uncover a role for the receptor in immunological tolerance.

B cell self-tolerance is maintained through multiple checkpoints, including restraints on intracellular signaling and cell trafficking. P2RY8 is a receptor with established roles in germinal center (GC) B cell migration inhibition and growth regulation. Somatic P2RY8 variants are common in GC-derived B cell lymphomas. Here, we identify germline novel or rare P2RY8 missense variants in lupus kindreds or the related antiphospholipid syndrome, including a "de novo" variant in a child with severe nephritis. All variants decreased protein expression, F-actin abundance, and GPCR-RhoA signaling, and those with stronger effects increased AKT and ERK activity and cell migration. Remarkably, P2RY8 was reduced in B cell subsets from some SLE patients lacking P2RY8 gene variants. Low P2RY8 correlated with lupus nephritis and increased age-associated B cells and plasma cells. By contrast, P2RY8 overexpression in cells and mice restrained plasma cell development and reinforced negative selection of DNA-reactive developing B cells. These findings uncover a role of P2RY8 in immunological tolerance and lupus pathogenesis.

Supporting Mental Health During the COVID-19 Pandemic Using a Digital Behavior Change Intervention: An Open-Label, Single-Arm, Pre-Post Intervention Study.

BACKGROUND: The COVID-19 pandemic is taking a toll on people's mental health, particularly as people are advised to adhere to social distancing, self-isolation measures, and government-imposed national lockdowns. Digital health technologies have an important role to play in keeping people connected and in supporting their mental health and well-being. Even before the COVID-19 pandemic, mental health and social services were already strained. OBJECTIVE: Our objective was to evaluate the 12-week outcomes of the digitally delivered Gro Health intervention, a holistic digital behavior change app designed for self-management of mental well-being, sleep, activity, and nutrition. METHODS: The study used a quasi-experimental research design consisting of an open-label, single-arm, pre-post intervention engagement using a convenience sample. Adults who had joined the Gro Health app (intervention) and had a complete baseline dataset (ie, 7-item Generalized Anxiety Disorder scale, Perceived Stress Scale, and 9-item Patient Health Questionnaire) were followed up at 12 weeks (n=273), including 33 (12.1%) app users who reported a positive COVID-19 diagnosis during the study period. User engagement with the Gro Health platform was tracked by measuring total minutes of app engagement. Paired t tests were used to compare pre-post intervention scores. Linear regression analysis was performed to assess the relationship between minutes of active engagement with the Gro Health app and changes in scores across the different mental health measures. RESULTS: Of the 347 study participants, 273 (78.67%) completed both the baseline and follow-up surveys. Changes in scores for anxiety, perceived stress, and depression were predicted by app engagement, with the strongest effect observed for changes in perceived stress score (F1,271=251.397; R2=0.479; P<.001). CONCLUSIONS: A digital behavior change platform that provides remote mental well-being support can be effective in managing depression, anxiety, and perceived stress during times of crisis such as the current COVID-19 pandemic. The outcomes of this study may also support the implementation of remote digital health apps supporting behavior change and providing support for low levels of mental health within the community.

Characterization of a Novel ACE2-Based Therapeutic with Enhanced Rather than Reduced Activity against SARS-CoV-2 Variants.

The human angiotensin-converting enzyme 2 acts as the host cell receptor for SARS-CoV-2 and the other members of the Coronaviridae family SARS-CoV-1 and HCoV-NL63. Here, we report the biophysical properties of the SARS-CoV-2 spike variants D614G, B.1.1.7, B.1.351, and P.1 with affinities to the ACE2 receptor and infectivity capacity, revealing weaknesses in the developed neutralizing antibody approaches. Furthermore, we report a preclinical characterization package for a soluble receptor decoy engineered to be catalytically inactive and immunologically inert, with broad neutralization capacity, that represents an attractive therapeutic alternative in light of the mutational landscape of COVID-19. This construct efficiently neutralized four SARS-CoV-2 variants of concern. The decoy also displays antibody-like biophysical properties and manufacturability, strengthening its suitability as a first-line treatment option in prophylaxis or therapeutic regimens for COVID-19 and related viral infections. IMPORTANCE Mutational drift of SARS-CoV-2 risks rendering both therapeutics and vaccines less effective. Receptor decoy strategies utilizing soluble human ACE2 may overcome the risk of viral mutational escape since mutations disrupting viral interaction with the ACE2 decoy will by necessity decrease virulence, thereby preventing meaningful escape. The solution described here of a soluble ACE2 receptor decoy is significant for the following reasons: while previous ACE2-based therapeutics have been described, ours has novel features, including (i) mutations within ACE2 to remove catalytical activity and systemic interference with the renin/angiotensin system, (ii) abrogated FcγR engagement, reduced risk of antibody-dependent enhancement of infection, and reduced risk of hyperinflammation, and (iii) streamlined antibody-like purification process and scale-up manufacturability indicating that this receptor decoy could be produced quickly and easily at scale. Finally, we demonstrate that ACE2-based therapeutics confer a broad-spectrum neutralization potency for ACE2-tropic viruses, including SARS-CoV-2 variants of concern in contrast to therapeutic MAb.

Ischaemic stroke and transient ischaemic attack on anticoagulants: outcomes in the era of direct oral anticoagulants.

Clinical and imaging characteristics of patients receiving direct oral anticoagulants presenting with transient ischaemic attack or stroke are lacking. A retrospective review of all patients who presented to a high-volume primary stroke centre with acute stroke symptoms while prescribed an oral anticoagulant between January 2012 and June 2017. Clinical, radiological characteristics and functional outcomes were examined. Anticoagulated patients diagnosed with stroke or transient ischaemic attack shared similar disease and outcome characteristics irrespective of anticoagulants used. One-third of warfarin patients with sub-therapeutic international normalised ratios were treated with thrombolytics but no direct oral anticoagulants level was performed in any of the patients, with only one treated by intravenous thrombolysis.

Functional rare and low frequency variants in BLK and BANK1 contribute to human lupus.

Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease. It is thought that many common variant gene loci of weak effect act additively to predispose to common autoimmune diseases, while the contribution of rare variants remains unclear. Here we describe that rare coding variants in lupus-risk genes are present in most SLE patients and healthy controls. We demonstrate the functional consequences of rare and low frequency missense variants in the interacting proteins BLK and BANK1, which are present alone, or in combination, in a substantial proportion of lupus patients. The rare variants found in patients, but not those found exclusively in controls, impair suppression of IRF5 and type-I IFN in human B cell lines and increase pathogenic lymphocytes in lupus-prone mice. Thus, rare gene variants are common in SLE and likely contribute to genetic risk.

MRI-guided adaptive brachytherapy for locally advanced cervix cancer: Treatment outcomes from a single institution in Hong Kong.

BACKGROUND: Paradigm has shifted from 2D to image-guided adaptive brachytherapy (IGABT) for locally advanced cervix cancer (LACC). Increasing reports from pioneering institutions and large retrospective multicenter series have demonstrated improvements in outcome and reduction in toxicity with IGABT. However, there is scarcity of data on magnetic resonance (MR)-IGABT in Chinese patients. PURPOSE: To evaluate the clinical outcome of MR-IGABT for LACC in a single institution in Hong Kong. MATERIAL AND METHODS: Patients with FIGO stage IB-IVA LACC treated with definitive external beam radiotherapy +/- concurrent cisplatin followed by MR-IGABT from January 2015 to January 2018 were included. Brachytherapy planning and dose reporting followed the GEC-ESTRO recommendations. Dosimetric and clinical outcomes including local control (LC), pelvic control (PC), cancer-specific survival, overall survival (OS), and toxicity were analyzed. RESULTS: Forty-two consecutive patients were included. 71% were FIGO stage IIB or above; 52% had pelvic node involvement. Median high-risk clinical target volume (HRCTV) was 34.7 cm3 (12.3-155.1 cm3). Median dose to HRCTV D90 was 88.5 Gy (63.4-113.4 Gy) (EQD210). Median doses to the D2cc of bladder, rectum, sigmoid, and small bowel were 83.1 Gy, 67.5 Gy, 69.0 Gy, and 68.9 Gy (EQD23), respectively. Median followup was 20.3 months (4.0-35.1 months). 24-month actuarial LC, PC, cancer-specific survival, and OS were 90%, 84%, 90%, and 90%, respectively. Stratification by clinical variables showed that FIGO stage had significant impact on LC and dose to HRCTV on both LC and PC. Treatment was well tolerated without any severe late toxicity. CONCLUSIONS: Intermediate-term results from systematic MR-IGABT for LACC demonstrate very promising outcomes with minimal toxicity. This fills the gap in evidence for MR-IGABT in Chinese patients.

Paradoxical embolism: role of imaging in diagnosis and treatment planning.

Paradoxical embolism (PDE) is an uncommon cause of acute arterial occlusion that may have catastrophic sequelae. The possibility of its presence should be considered in all patients with an arterial embolus in the absence of a cardiac or proximal arterial source. Despite advancements in radiologic imaging technology, the use of various complementary modalities is usually necessary to exclude other possibilities from the differential diagnosis and achieve an accurate imaging-based diagnosis of PDE. In current practice, the imaging workup of a patient with symptoms of PDE usually starts with computed tomography (CT) and magnetic resonance (MR) imaging to identify the cause of the symptoms and any thromboembolic complications in target organs (eg, stroke, peripheral arterial occlusion, or visceral organ ischemia). Additional imaging studies with modalities such as peripheral venous Doppler ultrasonography (US), transcranial Doppler US, echocardiography, and CT or MR imaging are required to detect peripheral and central sources of embolism, identify cardiac and/or extracardiac shunts, and determine whether arterial disease is present. To guide radiologists in selecting the optimal modalities for use in various diagnostic settings, the article provides detailed information about the imaging of PDE, with numerous radiologic and pathologic images illustrating the wide variety of features that may accompany and contribute to the pathologic process. The roles of CT and MR imaging in the diagnosis and exclusion of PDE are described, and the use of imaging for planning surgical treatment and interventional procedures is discussed.

Responding to pediatric providers' perceived barriers to adolescent weight management.

Primary care clinics are an ideal setting for early identification and possibly treatment of adolescent obesity. However, despite practice recommendations promoting preventive screening and monitoring of obesity, implementation has been modest. In this study, we interviewed providers to determine barriers to managing pediatric obesity, perceived skill in obesity interventions, and interest in additional training. The sensitivity of weight-related discussions and time were the 2 most significant barriers reported. We designed a brief training program, implemented it within a larger randomized controlled trial, and surveyed providers regarding its utility. The training was satisfactory to attendees and led to reported changes in practice patterns. Providers who received more complete training reported greater ease working with overweight teens and greater confidence that they could motivate teen patients to make healthy lifestyle changes compared with those who received less training. A fairly modest training intervention could improve patient care in the primary care setting.

A primary care-based, multicomponent lifestyle intervention for overweight adolescent females.

BACKGROUND AND OBJECTIVE: Most clinic-based weight control treatments for youth have been designed for preadolescent children by using family-based care. However, as adolescents become more autonomous and less motivated by parental influence, this strategy may be less appropriate. This study evaluated a primary care-based, multicomponent lifestyle intervention specifically tailored for overweight adolescent females. METHODS: Adolescent girls (N = 208) 12 to 17 years of age (mean ± SD: 14.1 ± 1.4 years), with a mean ± SD BMI percentile of 97.09 ± 2.27, were assigned randomly to the intervention or usual care control group. The gender and developmentally tailored intervention included a focus on adoptable healthy lifestyle behaviors and was reinforced by ongoing feedback from the teen's primary care physician. Of those randomized, 195 (94%) completed the 6-month posttreatment assessment, and 173 (83%) completed the 12-month follow-up. The primary outcome was reduction in BMI z score. RESULTS: The decrease in BMI z score over time was significantly greater for intervention participants compared with usual care participants (-0.15 in BMI z score among intervention participants compared with -0.08 among usual care participants; P = .012). The 2 groups did not differ in secondary metabolic or psychosocial outcomes. Compared with usual care, intervention participants reported less reduction in frequency of family meals and less fast-food intake. CONCLUSIONS: A 5-month, medium-intensity, primary care-based, multicomponent behavioral intervention was associated with significant and sustained decreases in BMI z scores among obese adolescent girls compared with those receiving usual care.

CD133 as a marker for cancer stem cells: progresses and concerns.

Increasing evidence supports the cancer stem cell hypothesis, which postulates that cancer stem cells are responsible for tumor initiation, metastasis, and resistance to treatments. Therefore, they are the cells to target to cure a cancer. To study the behavior of cancer stem cells, markers for prospective isolation of cancer stem cells are crucial. Recently, CD133 has been used extensively as a marker for the identification of stem cells from normal and cancerous tissues. Several more recent studies, however, indicate that CD133 are expressed in differentiated epithelial cells in various organs, and CD133-negative cancer cells can also initiate tumors. The findings suggest that CD133 is not restricted to somatic stem cells and cancer stem cells. However, in many cases CD133 may be used in combination with other markers or methods to acquire stem cells. In this review, we summarize findings in CD133 expression in various tissues and critically discuss its applications in stem cell isolation.

Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing.

Bone marrow derived mesenchymal stem cells (BM-MSCs) have been shown to enhance wound healing; however, the mechanisms involved are barely understood. In this study, we examined paracrine factors released by BM-MSCs and their effects on the cells participating in wound healing compared to those released by dermal fibroblasts. Analyses of BM-MSCs with Real-Time PCR and of BM-MSC-conditioned medium by antibody-based protein array and ELISA indicated that BM-MSCs secreted distinctively different cytokines and chemokines, such as greater amounts of VEGF-alpha, IGF-1, EGF, keratinocyte growth factor, angiopoietin-1, stromal derived factor-1, macrophage inflammatory protein-1alpha and beta and erythropoietin, compared to dermal fibroblasts. These molecules are known to be important in normal wound healing. BM-MSC-conditioned medium significantly enhanced migration of macrophages, keratinocytes and endothelial cells and proliferation of keratinocytes and endothelial cells compared to fibroblast-conditioned medium. Moreover, in a mouse model of excisional wound healing, where concentrated BM-MSC-conditioned medium was applied, accelerated wound healing occurred compared to administration of pre-conditioned or fibroblast-conditioned medium. Analysis of cell suspensions derived from the wound by FACS showed that wounds treated with BM-MSC-conditioned medium had increased proportions of CD4/80-positive macrophages and Flk-1-, CD34- or c-kit-positive endothelial (progenitor) cells compared to wounds treated with pre-conditioned medium or fibroblast-conditioned medium. Consistent with the above findings, immunohistochemical analysis of wound sections showed that wounds treated with BM-MSC-conditioned medium had increased abundance of macrophages. Our results suggest that factors released by BM-MSCs recruit macrophages and endothelial lineage cells into the wound thus enhancing wound healing.