Use of F18 bioglass putty for induced membrane technique in segmental bone defect of the radius in rabbits.

PURPOSE: To evaluate the inductive capacity of F18 bioglass putty on the induced membrane technique in a segmental bone defect of the rabbit's radius. METHODS: Ten female Norfolk at 24 months of age were used. The animals were randomly separated based on postoperative time points: five rabbits at 21 and four at 42 days. A 1-cm segmental bone defect was created in both radii. The bone defects were filled with an F18 bioglass putty. RESULTS: Immediate postoperative radiographic examination revealed the biomaterial occupying the segmental bone defect as a well-defined radiopaque structure with a density close to bone tissue. At 21 and 42 days after surgery, a reduction in radiopacity and volume of the biomaterial was observed, with particle dispersion in the bone defect region. Histologically, the induced membrane was verified in all animals, predominantly composed of fibrocollagenous tissue. In addition, chondroid and osteoid matrices undergoing regeneration, a densely vascularized tissue, and a foreign body type reaction composed of macrophages and multinucleated giant cells were seen. CONCLUSIONS: the F18 bioglass putty caused a foreign body-type inflammatory response with the development of an induced membrane without expansion capacity to perform the second stage of the Masquelet technique.

Metabolic effects of an oral carbohydrate-whey protein supplement after fasting in volunteers: A randomized controlled crossover trial.

OBJECTIVE: Oral supplements containing carbohydrates (CHOs) can be used to reduce preoperative fasting time. The aim of this study was to investigate the early metabolic and acute phase responses to a clear, oral supplement containing CHO and whey protein (WP) in young, healthy volunteers during a fasting-induced organic response. METHODS: In this controlled crossover clinical trial, volunteers were randomized into groups after a 12-h fast: the CHO+WP group consumed 200 mL CHO enriched with WP (n = 30); the CHO group members consumed 200 mL water plus maltodextrin (n = 30), and the Fast group was fasted only (n = 30). Blood samples were collected after fasting and 3 h after ingestion of the supplement. The samples were analyzed for glucose, glycated hemoglobin, insulin, C-reactive protein, ß-hydroxybutyrate, triacylglycerols, albumin, chlorine, and sodium. After 7 d, the groups were inverted, so all volunteers entered the three groups. RESULTS: The nutritional intervention did not change the biochemical parameters related to the acute phase response or insulin resistance; however, there was a statistically significant reduction (P < 0.001) in serum ß-hydroxybutyrate in the CHO+WP group (0.05 ± 0.08 mmol/L) compared with the other two groups (Fast group: 0.11 ± 0.08 mmol/L; CHO group: 0.09 ± 0.13 mmol/L). CONCLUSIONS: After overnight fasting, the oral supplement containing CHO and WP decreased ketosis. These findings may help select the most efficient oral supplement to be given 2 to 3 h before elective surgeries.

Use of F18 bioglass putty for induced membrane technique in segmental bone defect of the radius in rabbits

Purpose: To evaluate the inductive capacity of F18 bioglass putty on the induced membrane technique in a segmental bone defect of the rabbit's radius. Methods: Ten female Norfolk at 24 months of age were used. The animals were randomly separated based on postoperative time points: five rabbits at 21 and four at 42 days. A 1-cm segmental bone defect was created in both radii. The bone defects were filled with an F18 bioglass putty. Results: Immediate postoperative radiographic examination revealed the biomaterial occupying the segmental bone defect as a well-defined radiopaque structure with a density close to bone tissue. At 21 and 42 days after surgery, a reduction in radiopacity and volume of the biomaterial was observed, with particle dispersion in the bone defect region. Histologically, the induced membrane was verified in all animals, predominantly composed of fibrocollagenous tissue. In addition, chondroid and osteoid matrices undergoing regeneration, a densely vascularized tissue, and a foreign body type reaction composed of macrophages and multinucleated giant cells were seen. Conclusions: the F18 bioglass putty caused a foreign body-type inflammatory response with the development of an induced membrane without expansion capacity to perform the second stage of the Masquelet technique.

Corrigendum: Consistent long-term therapeutic efficacy of human umbilical cord matrix-derived mesenchymal stromal cells after myocardial infarction despite individual differences and transient engraftment.

[This corrects the article DOI: 10.3389/fcell.2021.624601.].

Human-umbilical cord matrix mesenchymal cells improved left ventricular contractility independently of infarct size in swine myocardial infarction with reperfusion.

Background: Human umbilical cord matrix-mesenchymal stromal cells (hUCM-MSC) have demonstrated beneficial effects in experimental acute myocardial infarction (AMI). Reperfusion injury hampers myocardial recovery in a clinical setting and its management is an unmet need. We investigated the efficacy of intracoronary (IC) delivery of xenogeneic hUCM-MSC as reperfusion-adjuvant therapy in a translational model of AMI in swine. Methods: In a placebo-controlled trial, pot-belied pigs were randomly assigned to a sham-control group (vehicle-injection; n = 8), AMI + vehicle (n = 12) or AMI + IC-injection (n = 11) of 5 × 105 hUCM-MSC/Kg, within 30 min of reperfusion. AMI was created percutaneously by balloon occlusion of the mid-LAD. Left-ventricular function was blindly evaluated at 8-weeks by invasive pressure-volume loop analysis (primary endpoint). Mechanistic readouts included histology, strength-length relationship in skinned cardiomyocytes and gene expression analysis by RNA-sequencing. Results: As compared to vehicle, hUCM-MSC enhanced systolic function as shown by higher ejection fraction (65 ± 6% vs. 43 ± 4%; p = 0.0048), cardiac index (4.1 ± 0.4 vs. 3.1 ± 0.2 L/min/m2; p = 0.0378), preload recruitable stroke work (75 ± 13 vs. 36 ± 4 mmHg; p = 0.0256) and end-systolic elastance (2.8 ± 0.7 vs. 2.1 ± 0.4 mmHg*m2/ml; p = 0.0663). Infarct size was non-significantly lower in cell-treated animals (13.7 ± 2.2% vs. 15.9 ± 2.7%; Δ = -2.2%; p = 0.23), as was interstitial fibrosis and cardiomyocyte hypertrophy in the remote myocardium. Sarcomere active tension improved, and genes related to extracellular matrix remodelling (including MMP9, TIMP1 and PAI1), collagen fibril organization and glycosaminoglycan biosynthesis were downregulated in animals treated with hUCM-MSC. Conclusion: Intracoronary transfer of xenogeneic hUCM-MSC shortly after reperfusion improved left-ventricular systolic function, which could not be explained by the observed extent of infarct size reduction alone. Combined contributions of favourable modification of myocardial interstitial fibrosis, matrix remodelling and enhanced cardiomyocyte contractility in the remote myocardium may provide mechanistic insight for the biological effect.

Impact of Nutritional Management on Survival of Critically Ill Malnourished Patients with Refeeding Hypophosphatemia.

BACKGROUND: Early nutritional therapy may aggravate hypophosphatemia in critically ill patients. AIM: To investigate the influence of the type nutritional therapy on the survival of critically-ill malnourished patients at refeeding hypophosphatemia risk. METHODS: Retrospective cohort study including malnourished, critically-ill adults, admitted from June 2014-December 2017 in an intensive care unit (ICU) at a tertiary hospital. Refeeding hypophosphatemia risk was defined as low serum phosphorus levels (<2.5 mg/dL) seen at two timepoints: before the initiation and at day 4 of the nutritional therapy. Patients receiving enteral nutrition (EN) were compared with those receiving supplemental parenteral nutrition (SPN-EN plus parenteral nutrition). Primary outcome was 60 d survival. Secondary endpoint was the incidence of refeeding hypophosphatemia risk. RESULTS: We included 468-321 patients (68.6%) received EN and 147 (31.4%) received SPN. The mortality rate was 36.3% (n = 170). Refeeding hypophosphatemia risk was found in 116 (24.8%) patients before and in 177 (37.8%) at day 4 of nutritional therapy. The 60 d mean survival probability was greater for patients receiving SPN both before (42.4 vs. 22.4%, p = 0.005) and at day 4 (37.4 vs. 25.8%, p = 0.014) vs. patients receiving EN at the same timepoints. Cox regression showed a hazard ratio of 3.3 and 2.4 for patients at refeeding hypophosphatemia risk before and at day 4 of EN, respectively, compared to the SPN group at the same timepoints. CONCLUSION: Refeeding hypophosphatemia risk was frequent in malnourished ICU patients and the survival for patients receiving SPN seemed associated with better survival than EN only.

Extracellular Matrix-Based Approaches in Cardiac Regeneration: Challenges and Opportunities.

Cardiac development is characterized by the active proliferation of different cardiac cell types, in particular cardiomyocytes and endothelial cells, that eventually build the beating heart. In mammals, these cells lose their regenerative potential early after birth, representing a major obstacle to our current capacity to restore the myocardial structure and function after an injury. Increasing evidence indicates that the cardiac extracellular matrix (ECM) actively regulates and orchestrates the proliferation, differentiation, and migration of cardiac cells within the heart, and that any change in either the composition of the ECM or its mechanical properties ultimately affect the behavior of these cells throughout one's life. Thus, understanding the role of ECMs' proteins and related signaling pathways on cardiac cell proliferation is essential to develop effective strategies fostering the regeneration of a damaged heart. This review provides an overview of the components of the ECM and its mechanical properties, whose function in cardiac regeneration has been elucidated, with a major focus on the strengths and weaknesses of the experimental models so far exploited to demonstrate the actual pro-regenerative capacity of the components of the ECM and to translate this knowledge into new therapies.

Residual gastric volume after 3 h of the ingestion of an oral supplement containing carbohydrates alone or associated with whey protein: a randomized crossover pilot study.

BACKGROUND: New formulas including a nitrogenous source to maltodextrin have been reported as preoperative beverages 2-3 h before anesthesia in the elective procedure. Whey protein is a potential candidate for the composition of this clear oral supplement. This study aimed to investigate the gastric residual volume (GRV) of healthy volunteers 3 h after the ingestion of an oral supplement containing carbohydrates (CHO) alone or combined with whey protein (WP). METHODS: This crossover clinical trial design includes young, healthy male volunteers with normal body mass index. Magnetic resonance imaging (MRI) scan of the upper abdomen to measure the GRV was performed in the participants in three phases: (1) after a fasting period of 8 h; (2) immediately after the ingestion of 200 mL of a clear supplement containing: (2a) 10 g of WP and 54 g of CHO (74% glucose and 26% maltodextrin)-WP + CHO group or (2b) 12.5% maltodextrin (25 g)-CHO group; and (3) after 3 h of the ingestion of both types of supplements. A week interval was programmed between phases 2a and 2b. RESULTS: There was no significant difference (p = 0.91; within-group comparison) of the mean ± SD of the GRV between phase 1 (WP + CHO: 23.45 ± 14.01; CHO: 25.03 ± 15.17 cm3; p = 0.78; between-groups comparison) and phase 3 (WP + CHO: 25.66 ± 9.31; CHO: 23.45 ± 13.58 cm3, p = 0.86; between-groups comparison). The GRV of phase 2 (WP + CHO: 206.43 ± 23; CHO: 203.99 ± 12.18 cm3; p = 0.82; between-groups comparison) was significantly greater (p < 0.01; within-group comparison) than both other two phases. CONCLUSION: The GRV after 3 h of the ingestion of either WP + CHO or CHO oral supplement returns to basal fast condition implying that gastric emptying after this interval of time is significantly completed. TRIAL REGISTRATION: Registered and posted on the ClinicalTrials.gov public website with Identifier: NCT05573854.

Extending the benefit of nutrition intervention beyond the operative setting.

PURPOSE OF REVIEW: To provide an update of the recent evidence on the potential of perioperative nutritional interventions to benefit adult patients undergoing head and neck and digestive procedures. RECENT FINDINGS: Perioperative nutrition within multimodal prehabilitation programs improve postoperative outcomes. Perioperative fasting time can be reduced with beverages containing carbohydrate alone or blended with a nitrogenous source such as whey protein; this approach seems to be safe and improve outcome. The choice of protein-containing formula, as well as diet composition to be recommended early during the postoperative refeeding, can be optimized to reduce complications. Sarcopenia is an important risk factor for surgical patients, as such, prehabilitation along with preoperative nutrition is strongly advised. Perioperative supplementation with ß-hydroxy ß-methylbutyrate to mitigate sarcopenia requires further investigation. Although perioperative nutritional interventions reduce healthcare costs, recent data suggest it has been scarcely prescribed. SUMMARY: Nutritional intervention is key in multimodal programs of enhanced recovery after surgery to ensure better outcomes. Perioperative fasting should be shortened, and include clear fluids containing carbohydrates and protein, especially in the early postoperative period. Multimodal prehabilitation is key to mitigate sarcopenia. Action to improve knowledge on the cost-effectiveness of nutritional interventions in the perioperative setting are needed.

COST-EFFECTIVENESS OF THE USE OF ACERTO PROTOCOL IN MAJOR DIGESTIVE SURGERY.

OBJECTIVE: Hospital costs in surgery constitute a burden for the health system in all over the world. Multimodal protocols such as the ACERTO project enhance postoperative recovery. The aim of this study was to analyze the hospital costs in patients undergoing major digestive surgical procedures with or without the perioperative care strategies proposed by the ACERTO project. METHODS: Retrospective data from elective patients undergoing major digestive surgical procedures in a university hospital between January 2002 and December 2011 were collected. The investigation involved two phases: between January 2002 and December 2005, covering cases admitted before the implementation of the ACERTO protocol (pre-ACERTO period), and cases operated between January 2006 and December 2011, after implementation (ACERTO period). The primary outcome was the comparison of hospital costs between the two periods. As secondary end point, we compared length of stay (LOS), postoperative complications, surgical-site infection (SSI) rate, and mortality. RESULTS: We analyzed 381 patients (239 of the pre-ACERTO period and 142 of the ACERTO period) who underwent major procedures on the gastrointestinal tract. Patients operated after within the ACERTO protocol postoperative LOS had a median of 3 days shorter (p=0.001) when compared with pre-ACERTO period [median (IQR): 10 (12) days vs. 13 (12) days]. Mortality was similar between the two periods. Postoperative complications risk, however, was 29% greater (RR: 1.29; 95%CI 1.11-1.50) in the pre-ACERTO period (p=0.002). SSI risk was also greater in pre-ACERTO period (RR: 1.33; 95%CI 1.14-1.50). Costs (mean and SE) per patients were R$24,562.84 (1,349.33) before the implementation and R$19,912.81 (1,459.89) after the ACERTO protocol (p=0.02). CONCLUSION: The implementation of the ACERTO project in this University Hospital reduced the hospital costs in major digestive procedures. Moreover, the implementation of this modern perioperative care strategy also reduced postoperative complications, SSI risks, and LOS.

Intercellular transfer of miR-200c-3p impairs the angiogenic capacity of cardiac endothelial cells.

As mediators of intercellular communication, extracellular vesicles containing molecular cargo, such as microRNAs, are secreted by cells and taken up by recipient cells to influence their cellular phenotype and function. Here we report that cardiac stress-induced differential microRNA content, with miR-200c-3p being one of the most enriched, in cardiomyocyte-derived extracellular vesicles mediates functional cross-talk with endothelial cells. Silencing of miR-200c-3p in mice subjected to chronic increased cardiac pressure overload resulted in attenuated hypertrophy, smaller fibrotic areas, higher capillary density, and preserved cardiac ejection fraction. We were able to maximally rescue microvascular and cardiac function with very low doses of antagomir, which specifically silences miR-200c-3p expression in non-myocyte cells. Our results reveal vesicle transfer of miR-200c-3p from cardiomyocytes to cardiac endothelial cells, underlining the importance of cardiac intercellular communication in the pathophysiology of heart failure.

Gut Microbiome and Organ Fibrosis.

Fibrosis is a pathological process associated with most chronic inflammatory diseases. It is defined by an excessive deposition of extracellular matrix proteins and can affect nearly every tissue and organ system in the body. Fibroproliferative diseases, such as intestinal fibrosis, liver cirrhosis, progressive kidney disease and cardiovascular disease, often lead to severe organ damage and are a leading cause of morbidity and mortality worldwide, for which there are currently no effective therapies available. In the past decade, a growing body of evidence has highlighted the gut microbiome as a major player in the regulation of the innate and adaptive immune system, with severe implications in the pathogenesis of multiple immune-mediated disorders. Gut microbiota dysbiosis has been associated with the development and progression of fibrotic processes in various organs and is predicted to be a potential therapeutic target for fibrosis management. In this review we summarize the state of the art concerning the crosstalk between intestinal microbiota and organ fibrosis, address the relevance of diet in different fibrotic diseases and discuss gut microbiome-targeted therapeutic approaches that are current being explored.

In vivo cyclic induction of the FOXM1 transcription factor delays natural and progeroid aging phenotypes and extends healthspan.

The FOXM1 transcription factor exhibits pleiotropic C-terminal transcriptional and N-terminal non-transcriptional functions in various biological processes critical for cellular homeostasis. We previously found that FOXM1 repression during cellular aging underlies the senescence phenotypes, which were vastly restored by overexpressing transcriptionally active FOXM1. Yet, it remains unknown whether increased expression of FOXM1 can delay organismal aging. Here, we show that in vivo cyclic induction of an N-terminal truncated FOXM1 transgene on progeroid and naturally aged mice offsets aging-associated repression of full-length endogenous Foxm1, reinstating both transcriptional and non-transcriptional functions. This translated into mitigation of several cellular aging hallmarks, as well as molecular and histopathological progeroid features of the short-lived Hutchison-Gilford progeria mouse model, significantly extending its lifespan. FOXM1 transgene induction also reinstated endogenous Foxm1 levels in naturally aged mice, delaying aging phenotypes while extending their lifespan. Thus, we disclose that FOXM1 genetic rewiring can delay senescence-associated progeroid and natural aging pathologies.

Cost-effectiveness of the use of acerto protocol in major digestive surgery / Custo-efetividade do uso do protocolo acerto em cirurgia digestiva de grande porte

ABSTRACT - BACKGROUND: Hospital costs in surgery constitute a burden for the health system in all over the world. Multimodal protocols such as the ACERTO project enhance postoperative recovery. OBJECTIVE: The aim of this study was to analyze the hospital costs in patients undergoing major digestive surgical procedures with or without the perioperative care strategies proposed by the ACERTO project. METHODS: Retrospective data from elective patients undergoing major digestive surgical procedures in a university hospital between January 2002 and December 2011 were collected. The investigation involved two phases: between January 2002 and December 2005, covering cases admitted before the implementation of the ACERTO protocol (pre-ACERTO period), and cases operated between January 2006 and December 2011, after implementation (ACERTO period). The primary outcome was the comparison of hospital costs between the two periods. As secondary end point, we compared length of stay (LOS), postoperative complications, surgical-site infection (SSI) rate, and mortality. RESULTS: We analyzed 381 patients (239 of the pre-ACERTO period and 142 of the ACERTO period) who underwent major procedures on the gastrointestinal tract. Patients operated after within the ACERTO protocol postoperative LOS had a median of 3 days shorter (p=0.001) when compared with pre-ACERTO period [median (IQR): 10 (12) days vs. 13 (12) days]. Mortality was similar between the two periods. Postoperative complications risk, however, was 29% greater (RR: 1.29; 95%CI 1.11-1.50) in the pre-ACERTO period (p=0.002). SSI risk was also greater in pre-ACERTO period (RR: 1.33; 95%CI 1.14-1.50). Costs (mean and SE) per patients were R$24,562.84 (1,349.33) before the implementation and R$19,912.81 (1,459.89) after the ACERTO protocol (p=0.02). CONCLUSION: The implementation of the ACERTO project in this University Hospital reduced the hospital costs in major digestive procedures. Moreover, the implementation of this modern perioperative care strategy also reduced postoperative complications, SSI risks, and LOS.

RESUMO - RACIONAL: Custos hospitalares em cirurgia constituem um peso para o sistema de saúde. Protocolos multimodais como o projeto ACERTO aceleram a recuperação pós-operatória. OBJETIVO: O objetivo deste estudo foi o de analisar custos hospitalares em pacientes submetidos a procedimentos cirúrgicos de grande porte no aparelho digestivo com ou sem as estratégias de cuidados perioperatórios proposta pelo projeto ACERTO. MÉTODOS: Foram coletados dados retrospectivos de pacientes eletivos submetidos a procedimentos cirúrgicos de grande porte no aparelho digestivo em um Hospital Universitário entre Janeiro de 2002 e Dezembro de 2011. O estudo envolveu duas fases: Entre Janeiro de 2002 a Dezembro 2005 envolvendo casos internados antes da implementação do protocolo ACERTO (período pré-ACERTO) e casos operados entre Janeiro de 2006 a Dezembro de 2011, após a implementação (período ACERTO). O desfecho primário foi a comparação de custos hospitalares entre os dois períodos. Como desfechos secundários, comparou-se o tempo de internação (LOS), complicações pós-operatórias, taxa de infecção de sitio cirúrgico (ISS) e a mortalidade. RESULTADOS: Foram analisados 381 pacientes (239 do período pré-ACERTO e 142 do período ACERTO) submetidos a procedimento cirúrgicos de grande porte no trato gastrointestinal. Pacientes operados dentro do protocolo ACERTO apresentaram mediana (IQR) mediana de tempo de internação três dias menor (p=0.001) quando comparados ao período pré-ACERTO (mediana (IQR): 10 (12) vs. 13 (12) dias). A mortalidade foi similar entre os dois períodos. Entretanto, o risco de complicações pós-operatórias foi 29% maior (RR: 1.29; IC95%: 1.11 - 1.50) no período pré-ACERTO (p=0.002). O risco de SSI também foi maior no período pré-ACERTO (RR: 1.33; 95%CI: 1.14-1.50). Custos (media e SE) per paciente foram de R$ 24562,84 (1349,33) antes da implementação e R$ 19912,81 (1459,89) após o protocolo ACERTO (p=0.02). CONCLUSÕES: A implementação do projeto ACERTO neste hospital universitário reduziu custos hospitalares em cirurgias digestivas de grande porte. Além disso, a prescrição de estratégias modernas de cuidados perioperatórios também reduziu riscos de complicações pós-operatórias e de SSI e o tempo de internação.

TLR4 Antagonism Reduces Movement-Induced Nociception and ATF-3 Expression in Experimental Osteoarthritis.

INTRODUCTION: Toll-like receptor 4 (TLR4) is a pattern recognition receptor involved in the detection of pathogen-associated molecular patterns (PAMPs), but also a "danger-sensing" receptor that recognizes host-derived endogenous molecules called damage-associated molecular patterns (DAMPs). The involvement of TLR4 in rheumatic diseases is becoming evident, as well as its potential role as a target for therapeutic intervention. Moreover, increasing evidence also suggests that TLR4 is implicated in chronic pain states. Thus, in this study, we evaluated whether a systemic administration of a synthetic antagonist of TLR4 (TLR4-A1) could decrease nociception and cartilage degradation in experimental osteoarthritis (OA). Furthermore, as the activation transcription factor (ATF)-3 serves as a negative regulator for TLR4-stimulated inflammatory response, we also evaluated the effect of TLR4 inhibition on ATF-3 expression in primary afferent neurons at the dorsal root ganglia (DRG). METHODS: OA was induced in adult male Wistar rats through an intra-articular injection of 2 mg of sodium mono-iodoacetate (MIA) into the left knee. From days 14 to 28 after OA induction, animals received an intraperitoneal injection of either TLR4-A1 (10 mg/kg) or vehicle. Movement- and loading-induced nociception was evaluated in all animals, by the Knee-Bend and CatWalk tests, before and at several time-points after TLR4-A1/vehicle administration. Immunofluorescence for TLR4 and ATF-3 was performed in L3-L5 DRG. Knee joints were processed for histopathological evaluation. RESULTS: Administration of TLR4-A1 markedly reduced movement-induced nociception in OA animals, particularly in the Knee-Bend test. Moreover, the increase of ATF-3 expression observed in DRG of OA animals was significantly reduced by TLR4-A1. However, no effect was observed in cartilage loss nor in the neuronal cytoplasmic expression of TLR4 upon antagonist administration. CONCLUSION: The TLR4 antagonist administration possibly interrupts the TLR4 signalling cascade, thus decreasing the neurotoxic environment at the joint, which leads to a reduction in ATF-3 expression and in nociception associated with experimental OA.

The bright side of fibroblasts: molecular signature and regenerative cues in major organs.

Fibrosis is a pathologic process characterized by the replacement of parenchymal tissue by large amounts of extracellular matrix, which may lead to organ dysfunction and even death. Fibroblasts are classically associated to fibrosis and tissue repair, and seldom to regeneration. However, accumulating evidence supports a pro-regenerative role of fibroblasts in different organs. While some organs rely on fibroblasts for maintaining stem cell niches, others depend on fibroblast activity, particularly on secreted molecules that promote cell adhesion, migration, and proliferation, to guide the regenerative process. Herein we provide an up-to-date overview of fibroblast-derived regenerative signaling across different organs and discuss how this capacity may become compromised with aging. We further introduce a new paradigm for regenerative therapies based on reverting adult fibroblasts to a fetal/neonatal-like phenotype.

A microRNA program regulates the balance between cardiomyocyte hyperplasia and hypertrophy and stimulates cardiac regeneration.

Myocardial regeneration is restricted to early postnatal life, when mammalian cardiomyocytes still retain the ability to proliferate. The molecular cues that induce cell cycle arrest of neonatal cardiomyocytes towards terminally differentiated adult heart muscle cells remain obscure. Here we report that the miR-106b~25 cluster is higher expressed in the early postnatal myocardium and decreases in expression towards adulthood, especially under conditions of overload, and orchestrates the transition of cardiomyocyte hyperplasia towards cell cycle arrest and hypertrophy by virtue of its targetome. In line, gene delivery of miR-106b~25 to the mouse heart provokes cardiomyocyte proliferation by targeting a network of negative cell cycle regulators including E2f5, Cdkn1c, Ccne1 and Wee1. Conversely, gene-targeted miR-106b~25 null mice display spontaneous hypertrophic remodeling and exaggerated remodeling to overload by derepression of the prohypertrophic transcription factors Hand2 and Mef2d. Taking advantage of the regulatory function of miR-106b~25 on cardiomyocyte hyperplasia and hypertrophy, viral gene delivery of miR-106b~25 provokes nearly complete regeneration of the adult myocardium after ischemic injury. Our data demonstrate that exploitation of conserved molecular programs can enhance the regenerative capacity of the injured heart.

Human umbilical cord tissue-derived mesenchymal stromal cells as adjuvant therapy for myocardial infarction: a review of current evidence focusing on pre-clinical large animal models and early human trials.

Although biologically appealing, the concept of tissue regeneration underlying first- and second-generation cell therapies has failed to translate into consistent results in clinical trials. Several types of cells from different origins have been tested in pre-clinical models and in patients with acute myocardial infarction (AMI). Mesenchymal stromal cells (MSCs) have gained attention because of their potential for immune modulation and ability to promote endogenous tissue repair, mainly through their secretome. MSCs can be easily obtained from several human tissues, the umbilical cord being the most abundant source, and further expanded in culture, making them attractive as an allogeneic "of-the-shelf" cell product, suitable for the AMI setting. The available evidence concerning umbilical cord-derived MSCs in AMI is reviewed, focusing on large animal pre-clinical studies and early human trials. Molecular and cellular mechanisms as well as current limitations and possible translational solutions are also discussed.