Protective role of RIPK1 scaffolding against HDV-induced hepatocyte cell death and the significance of cytokines in mice.

Hepatitis delta virus (HDV) infection represents the most severe form of human viral hepatitis; however, the mechanisms underlying its pathology remain incompletely understood. We recently developed an HDV mouse model by injecting adeno-associated viral vectors (AAV) containing replication-competent HBV and HDV genomes. This model replicates many features of human infection, including liver injury. Notably, the extent of liver damage can be diminished with anti-TNF-α treatment. Here, we found that TNF-α is mainly produced by macrophages. Downstream of the TNF-α receptor (TNFR), the receptor-interacting serine/threonine-protein kinase 1 (RIPK1) serves as a cell fate regulator, playing roles in both cell survival and death pathways. In this study, we explored the function of RIPK1 and other host factors in HDV-induced cell death. We determined that the scaffolding function of RIPK1, and not its kinase activity, offers partial protection against HDV-induced apoptosis. A reduction in RIPK1 expression in hepatocytes through CRISPR-Cas9-mediated gene editing significantly intensifies HDV-induced damage. Contrary to our expectations, the protective effect of RIPK1 was not linked to TNF-α or macrophage activation, as their absence did not alter the extent of damage. Intriguingly, in the absence of RIPK1, macrophages confer a protective role. However, in animals unresponsive to type-I IFNs, RIPK1 downregulation did not exacerbate the damage, suggesting RIPK1's role in shielding hepatocytes from type-I IFN-induced cell death. Interestingly, while the damage extent is similar between IFNα/ßR KO and wild type mice in terms of transaminase elevation, their cell death mechanisms differ. In conclusion, our findings reveal that HDV-induced type-I IFN production is central to inducing hepatocyte death, and RIPK1's scaffolding function offers protective benefits. Thus, type-I IFN together with TNF-α, contribute to HDV-induced liver damage. These insights may guide the development of novel therapeutic strategies to mitigate HDV-induced liver damage and halt disease progression.

Cardiac Progenitor Cell Exosomal miR-935 Protects against Oxidative Stress.

Oxidative stress-induced myocardial apoptosis and necrosis are critically involved in ischemic infarction, and several sources of extracellular vesicles appear to be enriched in therapeutic activities. The central objective was to identify and validate the differential exosome miRNA repertoire in human cardiac progenitor cells (CPC). CPC exosomes were first analyzed by LC-MS/MS and compared by RNAseq with exomes of human mesenchymal stromal cells and human fibroblasts to define their differential exosome miRNA repertoire (exo-miRSEL). Proteomics demonstrated a highly significant representation of cardiovascular development functions and angiogenesis in CPC exosomes, and RNAseq analysis yielded about 350 different miRNAs; among the exo-miRSEL population, miR-935 was confirmed as the miRNA most significantly up-regulated; interestingly, miR-935 was also found to be preferentially expressed in mouse primary cardiac Bmi1+high CPC, a population highly enriched in progenitors. Furthermore, it was found that transfection of an miR-935 antagomiR combined with oxidative stress treatment provoked a significant increment both in apoptotic and necrotic populations, whereas transfection of a miR-935 mimic did not modify the response. Conclusion. miR-935 is a highly differentially expressed miRNA in exo-miRSEL, and its expression reduction promotes oxidative stress-associated apoptosis. MiR-935, together with other exosomal miRNA members, could counteract oxidative stress-related apoptosis, at least in CPC surroundings.

Patient Insight With Collagenase Treatment for Dupuytren: A Prospective Study.

PURPOSE: There appears to be controversy regarding differing patient and physician perceptions of adverse effects (AEs) in the treatment of Dupuytren disease with collagenase clostridium histolyticum (CCH). The aim of this study was to compare the number, type, and severity of AEs perceived and reported by patients and by their physician METHODS: To assess AEs following CCH injection in a standardized way, patients were given a list of predefined complications and asked to rate their severity on a 4-point Likert scale ranging from 1 (serious) to 4 (insignificant). RESULTS: Eighty-five patients were included. Patients reported fewer AEs than their physician (mean, 1.48 vs 2.18). There was no agreement between physician- and patient-reported AEs except for skin lacerations, which showed fair agreement (κ = 0.257). CONCLUSIONS: Patients and physicians differ in their evaluation of AEs due to CCH treatment in Dupuytren disease. A fair level of agreement was observed for skin lacerations. CLINICAL RELEVANCE: Greater consensus is needed when defining AEs associated with CCH in the treatment of Dupuytren disease.

A comparison of patient-reported outcome measures for dupuytren disease: A prospective view.

Treatment success in Dupuytren´s disease has traditionally been assessed by clinical examination and physical measures, but based on patient orientation, patient-reported outcome measures (PROMs) can be used to quantify treatment impacts and health-related quality of life. The aim of this study was to compare the most widely used PROMS in Dupuytren´s disease, their psychometric properties, and their association with objectively measured hand function. We show a prospective study in which two disease-specific questionnaires (URAM scale and SDSS) and two hand-specific questionnaires (briefMHQ and PEM) were administered before and a month after the treatment with collagenase. Psychometric properties (construct validity, internal consistency, test-retest reliability, internal and external responsiveness, reliability, and minimal clinically important difference (MCID)) were calculated for all the questionnaires. Ninety-two completed both sets of questionnaires. Pre- and post-treatment scores were strongly correlated (Spearman rho >0.6) for all questionnaires. High internal consistency (Cronbach alpha >0.88) was observed for all the questionnaires. Test-retest reliability was also significant, with an ICC of >0.50 in all cases. The MCID was similar for three of the questionnaires (URAM, 11.528/45=0.256; SDSS, 5.079/20=0.254; and PEM, 21.542/77=0.215) and somewhat lower for the briefMHQ (10.617/60=0.177). No correlations were observed between treatment outcome and treated hand (r = 0.107; p = 0.31), joint (r = 0.163; p = 0.12), or finger (r = -0.151; p = 0.15). In conclusion, we did not find that any one questionnaire performed better than the other in detecting perceived changes in health status among patients with Dupuytren´s disease treated with collagenase.

The Vascular Niche for Adult Cardiac Progenitor Cells.

Research on cardiac progenitor cell populations has generated expectations about their potential for cardiac regeneration capacity after acute myocardial infarction and during physiological aging; however, the endogenous capacity of the adult mammalian heart is limited. The modest efficacy of exogenous cell-based treatments can guide the development of new approaches that, alone or in combination, can be applied to boost clinical efficacy. The identification and manipulation of the adult stem cell environment, termed niche, will be critical for providing new evidence on adult stem cell populations and improving stem-cell-based therapies. Here, we review and discuss the state of our understanding of the interaction of adult cardiac progenitor cells with other cardiac cell populations, with a focus on the description of the B-CPC progenitor population (Bmi1+ cardiac progenitor cell), which is a strong candidate progenitor for all main cardiac cell lineages, both in the steady state and after cardiac damage. The set of all interactions should be able to define the vascular cardiac stem cell niche, which is associated with low oxidative stress domains in vasculature, and whose manipulation would offer new hope in the cardiac regeneration field.

Sensitivity and Specificity of the Unité Rhumatologique Des Affections De La Main (URAM) Scale for Dupuytren Contracture: A Systematic Review and Meta-Analyses.

BACKGROUND: Unité Rhumatologique des Affections de la Main (URAM) is a novel and disease-specific questionnaire for Dupuytren contracture, a fibroproliferative disease that affects hands causing progressive contracture in flexion of the fingers. OBJECTIVES: To evaluate the sensitivity and specificity of the URAM scale in Dupuytren contracture. MATERIALS AND METHODS: We performed meta-analyses of 10 articles published in PubMed, Embase, Cochrane, Google Scholar, Latin American and Caribbean Health Sciences Literature (LILACS), and in various grey literature databases that describe the use of the URAM and Tubiana scales to assess treatment outcomes in Dupuytren contracture. We built three models: a hierarchical summary receiver operating characteristic (HSROC) model to determine the optimal threshold for defining Dupuytren contracture, a difference in means model to assess the magnitude of the effect of different treatment modalities, and a meta-regression model to determine the effect on patient quality of life questionnaires such as the URAM, according to variations in Tubiana scores after treatment. RESULTS: The HSROC and bivariate models showed a sensitivity of 80.23% (95% CI: 75.66 to 84.14) and an overall specificity of 2.61% (95% CI: 1.11 to 6.05). The second model showed an overall difference in means of 1.95 (95% CI: -2.86 to -1.04) for partial fasciectomy and collagenase Clostridium histolyticum (CCH) injections, and -1.30 (95% CI: -1.77 to -0.83) for partial fasciectomy, and -2.75 (95% CI: -4.73 to -0.78) for CCH. The coefficient obtained in the meta-regression model was -1.666 (95% CI: -4.183 to 0.851). CONCLUSION: The URAM scale is highly sensitive to changes in Dupuytren contracture but has low specificity. It also showed a strong correlation with worsening of finger contracture as measured by the Tubiana scale.

Neonatos en tratamiento con nutriciones parenterales individualizadas, candidatos a recibir nutriciones parenterales estandarizadas / Neonates treated with individualized parenteral nutrition who are candidates to receive standardized parenteral nutrition

OBJETIVO: cuantificar el número de pacientes neonatos en tratamiento con nutriciones parenterales individualizadas (NPI), candidatos a recibir nutriciones parenterales estandarizadas (NPE), así como el número de días. MATERIAL Y MÉTODOS: estudio prospectivo observacional y descriptivo de cohortes. Los criterios de inclusión fueron: pacientes neonatos con indicación de nutrición parenteral (NP) y prescripción individualizada. Los criterios de exclusión fueron: pacientes que no hubieran iniciado la diuresis, con necesidades nutricionales específicas, con alteraciones del equilibrio ácido-base y/o con contraindicación de la NPE. Se emplearon variables relacionadas con el paciente (sexo, peso, semanas de gestación y días de vida) y relacionadas con el tratamiento (aportes de la NPI). Fijando como criterio de conversión el volumen de NP, se calcularon los aportes teóricos con la NPE. El criterio para que un paciente fuera candidato a recibirla fue que todos los aportes teóricos estuvieran dentro de los requerimientos de referencia. RESULTADOS: se incluyeron 33 neonatos (9 mujeres) en tratamiento con NPI y con 94 prescripciones. La mediana de peso de los pacientes incluidos en el estudio fue de 2,14 (RIC: 0,9) kg, nacidos a las 35 (RIC: 3) semanas de gestación y en los que se inició NP entre los días 0 y 4. El 71 % (22/31) de los pacientes en el 54,1 % (46/85) de sus prescripciones fueron candidatos a recibir NPE administrada por vía central durante 1 a 8 días, mientras que ningún paciente fue candidato a recibirla por vía periférica. CONCLUSIONES: en nuestro centro, el 71 % de los pacientes nenonatos en tratamiento con NPI administrada por vía central son candidatos a recibir NPE, lo que fomenta la normalización del soporte nutricional en esta población

OBJETIVE: to quantify the number of neonates treated with individualized parenteral nutrition (IPN) who were candidates to receive standardized parenteral nutrition (SPN), and to calculate their treatment duration. MATERIAL AND METHODS: this was a prospective, observational, descriptive cohort study. Inclusion criteria were: neonates with indication of parenteral nutrition (PN) and individualized prescription. Exclusion criteria included: patients who had not started diuresis, with specific nutritional needs, altered acid-base balance, and/or contraindication to receive SPN. Included variables were patient-related (gender, weight, weeks of gestation, and days of life) and treatment-related regarding IPN composition. Setting the volume of PN as the conversion criterion, theoretical contributions were calculated with the SPN. The criterion for a patient to be a candidate to receive SPN was that all the theoretical contributions calculated were within the reference requirements range. RESULTS: a total of 33 neonates (9 women) received IPN with 94 prescriptions. The median weight of the patients included in the study was 2.14 (IQR, 0.9) kg, and they were born at 35 (IQR, 3) weeks of gestation. PN began between 0 and 4 days of life. In all, 71 % (22/31) of the patients in 54.1 % of their (46/85) prescriptions were candidates to receive SPN via central administration for 1 to 8 days, whereas no patient was candidate to receive SPN via peripheral administration. CONCLUSIONS: in our center, 71 % of neonates treated with central administration of IPN are candidates to receive SPN, thus promoting the normalization of nutritional support in this population

[Neonates treated with individualized parenteral nutrition who are candidates to receive standardized parenteral nutrition]. / Neonatos en tratamiento con nutriciones parenterales individualizadas, candidatos a recibir nutriciones parenterales estandarizadas.

INTRODUCTION: Objetive: to quantify the number of neonates treated with individualized parenteral nutrition (IPN) who were candidates to receive standardized parenteral nutrition (SPN), and to calculate their treatment duration. Material and methods: this was a prospective, observational, descriptive cohort study. Inclusion criteria were: neonates with indication of parenteral nutrition (PN) and individualized prescription. Exclusion criteria included: patients who had not started diuresis, with specific nutritional needs, altered acid-base balance, and/or contraindication to receive SPN. Included variables were patient-related (gender, weight, weeks of gestation, and days of life) and treatment-related regarding IPN composition. Setting the volume of PN as the conversion criterion, theoretical contributions were calculated with the SPN. The criterion for a patient to be a candidate to receive SPN was that all the theoretical contributions calculated were within the reference requirements range. Results: a total of 33 neonates (9 women) received IPN with 94 prescriptions. The median weight of the patients included in the study was 2.14 (IQR, 0.9) kg, and they were born at 35 (IQR, 3) weeks of gestation. PN began between 0 and 4 days of life. In all, 71 % (22/31) of the patients in 54.1 % of their (46/85) prescriptions were candidates to receive SPN via central administration for 1 to 8 days, whereas no patient was candidate to receive SPN via peripheral administration. Conclusions: in our center, 71 % of neonates treated with central administration of IPN are candidates to receive SPN, thus promoting the normalization of nutritional support in this population.

INTRODUCCIÓN: Objetivo: cuantificar el número de pacientes neonatos en tratamiento con nutriciones parenterales individualizadas (NPI), candidatos a recibir nutriciones parenterales estandarizadas (NPE), así como el número de días. Material y métodos: estudio prospectivo observacional y descriptivo de cohortes. Los criterios de inclusión fueron: pacientes neonatos con indicación de nutrición parenteral (NP) y prescripción individualizada. Los criterios de exclusión fueron: pacientes que no hubieran iniciado la diuresis, con necesidades nutricionales específicas, con alteraciones del equilibrio ácido-base y/o con contraindicación de la NPE. Se emplearon variables relacionadas con el paciente (sexo, peso, semanas de gestación y días de vida) y relacionadas con el tratamiento (aportes de la NPI). Fijando como criterio de conversión el volumen de NP, se calcularon los aportes teóricos con la NPE. El criterio para que un paciente fuera candidato a recibirla fue que todos los aportes teóricos estuvieran dentro de los requerimientos de referencia. Resultados: se incluyeron 33 neonatos (9 mujeres) en tratamiento con NPI y con 94 prescripciones. La mediana de peso de los pacientes incluidos en el estudio fue de 2,14 (RIC: 0,9) kg, nacidos a las 35 (RIC: 3) semanas de gestación y en los que se inició NP entre los días 0 y 4. El 71 % (22/31) de los pacientes en el 54,1 % (46/85) de sus prescripciones fueron candidatos a recibir NPE administrada por vía central durante 1 a 8 días, mientras que ningún paciente fue candidato a recibirla por vía periférica. Conclusiones: en nuestro centro, el 71 % de los pacientes nenonatos en tratamiento con NPI administrada por vía central son candidatos a recibir NPE, lo que fomenta la normalización del soporte nutricional en esta población.

"Validation of a spanish version of the 'Unité Rhumatologique Des Affections De La Main' (URAM) scale".

BACKGROUND: In health care, quality-of-life surveys and questionnaires related to care are becoming increasingly important as a measure of its quality. There is currently no Spanish version of the Unité Rhumatologique des Affections de la Main (URAM) scale, which makes it suitable for hand pathology. The purposes of this study are to develop a Spanish version of the URAM and perform a transcultural adaptation of it, analyzing the result for reliability, validity, and sensitivity to changes. METHODS: The questionnaire was evaluated for patients with Dupuytren's disease and Carpal Tunnel Syndrome. The cohort study subjects were interviewed at three points in time (baseline, three days after intervention, and one month after), administering the QuickDASH, URAM, and SF-12 (CF12 = physical component, CM12 = mental component) questionnaires at baseline and after intervention; and only the URAM at 3 days. Content validity was evaluated using Cronbach's α. The distribution of the factorial loads of the items and the pattern of the answers were checked. Responsiveness was evaluated by the size of the effect and the reliable rate of change. Convergent and divergent validity was performed using Spearman's r between the different questionnaires. RESULTS: The study was conducted with 106 patients. The mean baseline scores were: URAM = 14.8, QuickDASH = 41.6, CF12 = 39.3 and CM12 = 49.4. Ceiling or floor effects were not observed in the Spanish URAM. The Cronbach α = 0.853 explains 49.6% of the variance. The study had a high reproducibility (intraclass correlation coefficient (ICC) = 0.939). Size effect, measured as differences in scores, was moderate for URAM (-0.69) and QuickDASH (-0.51); and low for CF12 and CM12. The correlation of URAM with QuickDASH was high (r = 0.716), and moderate with DD and CTS. CONCLUSION: The Spanish version of the URAM is a valid and reliable tool for use in assessing hand pathology.

Age-related oxidative stress confines damage-responsive Bmi1+ cells to perivascular regions in the murine adult heart.

Adult progenitor cells reside in specialized microenvironments which maintain their undifferentiated cell state and trigger regenerative responses following injury. Although these environments are well described in several tissues, the cellular components that comprise the cardiac environment where progenitor cells are located remain unknown. Here we use Bmi1CreERT and Bmi1GFP mice as genetic tools to trace cardiac damage-responsive cells throughout the mouse lifespan. In adolescent mice, Bmi1+ damage-responsive cells are broadly distributed throughout the myocardium. In adult mice, however, Bmi1+ cells are confined predominately in perivascular areas with low levels of reactive oxygen species (ROS) and their number decline in an age-dependent manner. In vitro co-culture experiments with endothelial cells supported a regulatory role of the endothelium in damage-responsive cell behavior. Accordingly, in vivo genetic decrease of ROS levels in adult heart disengaged Bmi1+ cells from the cardiovascular network, recapitulating an adolescent-like Bmi1 expression profile. Thus, we identify cardiac perivascular regions as low-stress microenvironments that favor the maintenance of adult damage-responsive cells.

Bmi1-Progenitor Cell Ablation Impairs the Angiogenic Response to Myocardial Infarction.

Objective- Cardiac progenitor cells reside in the heart in adulthood, although their physiological relevance remains unknown. Here, we demonstrate that after myocardial infarction, adult Bmi1+ (B lymphoma Mo-MLV insertion region 1 homolog [PCGF4]) cardiac cells are a key progenitor-like population in cardiac neovascularization during ventricular remodeling. Approach and Results- These cells, which have a strong in vivo differentiation bias, are a mixture of endothelial- and mesenchymal-related cells with in vitro spontaneous endothelial cell differentiation capacity. Genetic lineage tracing analysis showed that heart-resident Bmi1+ progenitor cells proliferate after acute myocardial infarction and differentiate to generate de novo cardiac vasculature. In a mouse model of induced myocardial infarction, genetic ablation of these cells substantially deteriorated both heart angiogenesis and the ejection fraction, resulting in an ischemic-dilated cardiac phenotype. Conclusions- These findings imply that endothelial-related Bmi1+ progenitor cells are necessary for injury-induced neovascularization in adult mouse heart and highlight these cells as a suitable therapeutic target for preventing dysfunctional left ventricular remodeling after injury.

Redox-dependent BMI1 activity drives in vivo adult cardiac progenitor cell differentiation.

Accumulation of reactive oxygen species (ROS) is associated with several cardiovascular pathologies and with cell cycle exit by neonanatal cardiomyocytes, a key limiting factor in the regenerative capacity of the adult mammalian heart. The polycomb complex component BMI1 is linked to adult progenitors and is an important partner in DNA repair and redox regulation. We found that high BMI1 expression is associated with an adult Sca1+ cardiac progenitor sub-population with low ROS levels. In homeostasis, BMI1 repressed cell fate genes, including a cardiogenic differentiation program. Oxidative damage nonetheless modified BMI1 activity in vivo by derepressing canonical target genes in favor of their antioxidant and anticlastogenic functions. This redox-mediated mechanism is not restricted to damage situations, however, and we report ROS-associated differentiation of cardiac progenitors in steady state. These findings demonstrate how redox status influences the cardiac progenitor response, and identify redox-mediated BMI1 regulation with implications in maintenance of cellular identity in vivo.

Polµ deficiency induces moderate shortening of P53-/- mouse lifespan and modifies tumor spectrum.

Non-homologous end joining (NHEJ) is the main mechanism for double strand break (DSB) DNA repair. The error-prone DNA polymerase mu (Polµ) is involved in immunoglobulin variable region rearrangement and in general, NHEJ in non-lymphoid cells. Deletion of NHEJ factors in P53-/- mice, which are highly prone to development of T cell lymphoma, generally increases cancer incidence and shifts the tumor spectrum towards aggressive pro-B lymphoma. In contrast, Polµ deletion increased sarcoma incidence, proportionally reducing pro-B lymphoma development on the P53-deficient background. Array comparative genomic hybridization (aCGH) analyses showed DNA copy number alterations in both P53-/- and Polµ-/-P53-/- lymphomas. Our results also indicate that the increase in sarcoma incidence in Polµ-/-P53-/- mice could be associated with Cdk4 and Kub3 amplification and overexpression. These results identify a role for Polµ in the prevention of sarcomagenesis on a murine P53-deficient background, in contrast to most other NHEJ factors.

Adverse Effects of Collagenase in the Treatment of Dupuytren Disease: A Systematic Review.

BACKGROUND: Collagenase clostridium histolyticum (CCH) has proven to be both safe and effective in the treatment of Dupuytren disease (DD). The medium-term outcomes are similar to those achieved with surgery, and most adverse effects are self-limiting and considered to be mild or moderate. OBJECTIVE: Our objective was to conduct a systematic review of the adverse effects of CCH in DD since the release of the drug to evaluate the incidence, severity, classification, and definitions of these effects. METHODS: We analyzed the literature in terms of modifications to the original treatment protocol and grouped adverse effects according to their pathophysiological origin. RESULTS: We included 28 clinical studies and five case reports or case series analyzing 4456 patients with a mean age of 63.6 years. Mean follow-up was 7.07 months (range 3-24); the mean number of patients per study was 148 (range 5-1082). The studies did not classify the adverse effects they reported into groups. The most common effects were peripheral edema (54.4%), bruising (42.9%), and upper limb pain (28.3%). Significant biases were observed for use of terminology, demarcation of sites of involvement, severity criteria, and assessment methods. CONCLUSION: A simpler and clearer consensus-based classification system would enable better evaluation and comparison of the adverse effects of CCH in the treatment of DD. Consideration of inflammatory phenomena as part of the drug's mechanism of action would significantly reduce overall rates of adverse effects.

Identification and Characterization of the Dermal Panniculus Carnosus Muscle Stem Cells.

The dermal Panniculus carnosus (PC) muscle is important for wound contraction in lower mammals and represents an interesting model of muscle regeneration due to its high cell turnover. The resident satellite cells (the bona fide muscle stem cells) remain poorly characterized. Here we analyzed PC satellite cells with regard to developmental origin and purported function. Lineage tracing shows that they originate in Myf5(+), Pax3/Pax7(+) cell populations. Skin and muscle wounding increased PC myofiber turnover, with the satellite cell progeny being involved in muscle regeneration but with no detectable contribution to the wound-bed myofibroblasts. Since hematopoietic stem cells fuse to PC myofibers in the absence of injury, we also studied the contribution of bone marrow-derived cells to the PC satellite cell compartment, demonstrating that cells of donor origin are capable of repopulating the PC muscle stem cell niche after irradiation and bone marrow transplantation but may not fully acquire the relevant myogenic commitment.

Bmi1 (+) cardiac progenitor cells contribute to myocardial repair following acute injury.

BACKGROUND: The inability of the adult mammalian heart to replace cells lost after severe cardiac injury compromises organ function. Although the heart is one of the least regenerative organs in the body, evidence accumulated in recent decades indicates a certain degree of renewal after injury. We have evaluated the role of cardiac Bmi1 (+) progenitor cells (Bmi1-CPC) following acute myocardial infarction (AMI). METHODS: Bmi1 (Cre/+);Rosa26 (YFP/+) (Bmi1-YFP) mice were used for lineage tracing strategy. After tamoxifen (TM) induction, yellow fluorescent protein (YFP) is expressed under the control of Rosa26 regulatory sequences in Bmi1 (+) cells. YFP(+) cells were tracked following myocardial infarction. Additionally, whole transcriptome analysis of isolated YFP(+) cells was performed in unchallenged hearts and after myocardial infarction. RESULTS: Deep-sequencing analysis of Bmi1-CPC from unchallenged hearts suggests that this population expresses high levels of pluripotency markers. Conversely, transcriptome evaluation of Bmi1-CPC following AMI shows a rich representation of genes related to cell proliferation, movement, and cell cycle. Lineage-tracing studies after cardiac infarction show that the progeny of Bmi1-expressing cells contribute to de novo cardiomyocytes (CM) (13.8 ± 5 % new YFP(+) CM compared to 4.7 ± 0.9 % in age-paired non-infarcted hearts). However, apical resection of TM-induced day 1 Bmi1-YFP pups indicated a very minor contribution of Bmi1-derived cells to de novo CM. CONCLUSIONS: Cardiac Bmi1 progenitor cells respond to cardiac injury, contributing to the generation of de novo CM in the adult mouse heart.