Street medicine: An interprofessional elective to address the unhoused population crisis.

BACKGROUND AND PURPOSE: The homelessness crisis continues to escalate nationwide, yet many healthcare providers are not adequately prepared to provide care for unhoused patients. An interprofessional Street Medicine elective was developed to address identified knowledge gaps in the unhoused population healthcare needs. EDUCATIONAL ACTIVITY AND SETTING: The course comprised didactic and clinical elements focused on empathetic communication, resource utilization, and medical management for unhoused patients. Course learning outcomes were evaluated via thematic analysis of students' post-course reflective essays. Additionally, students completed a voluntary survey to evaluate course effectiveness in preparing students for healthcare in the unhoused population and to identify areas for course improvement. FINDINGS: Thirty students completed the course (17 osteopathic medical, five pharmacy, eight joint physician assistant/public health). All enrolled students submitted mandatory post-course reflections and 57% completed the voluntary survey. Thematic analysis of reflections indicated that the course content challenged biases toward unhoused populations, equipped students with new perspectives on the unique healthcare needs for unhoused patients, and provided interprofessional approaches to address these needs. Voluntary survey results demonstrated students' preparedness to provide effective care for local unhoused patients without bias or stigma. Most students reported they were likely to incorporate the knowledge/skills acquired from the course in their future clinical practice and were satisfied with the course content and organization. SUMMARY: The Street Medicine elective provided a structured interprofessional curricular opportunity on specialized care for unhoused individuals. This course can be adapted by other healthcare professional programs to empower students to address the growing homelessness crisis.

Nutrition and Lifestyle Coaching: An Interprofessional Course for Pharmacy, Medical, and Dietetic Students.

Background Poor nutrition and lifestyle choices are major contributors to the development and progression of various chronic diseases. Enhancing patients' awareness of healthy nutrition and lifestyle habits by interprofessional healthcare teams can play a significant role in tackling many chronic diseases, particularly in underserved communities with inequitable access to healthcare and educational opportunities. However, healthcare professionals are not adequately prepared to provide effective, culturally competent nutrition and lifestyle coaching due to a lack of emphasis on these topics in the curricula of many healthcare professional programs. Objective This study introduces a virtual, interprofessional, team-based elective course to address the curricular gap in nutrition education among healthcare professional programs. Methods Quantitative and qualitative pre-/post-surveys were utilized to evaluate course impact on student's knowledge, confidence in coaching families, and interprofessional competencies. Quantitative pre-/post-training scores were analyzed by a two-tailed, Mann-Whitney test, where P < 0.05 indicated a significant difference. Additionally, student learning outcomes were assessed using readiness assurance tests and application exercises, along with end-of-course presentations and mock interviews. Results Pre-/post-course assessments (n = 16) demonstrated significant improvement in students' confidence in coaching families (20%; P = 0.01) and knowledge of coaching curriculum (87%; P < 0.001). Improvement in different interprofessional competencies ranged between 15% (P = 0.002) and 46% (P < 0.001). Course material/activities, facilitation, impact on learning new knowledge/skills/mindset, and application in future practice were applauded by 81-94% of students. Conclusion Positive outcomes of this course encourage future offerings and systematic incorporation of similar training in healthcare professional programs to prepare clinicians capable of transforming lives through interprofessional, patient-centered nutrition and lifestyle coaching.

Racial, Ethnic, and Sex Diversity Trends in Health Professions Programs From Applicants to Graduates.

Importance: Diversity is an essential element of an effective health care system. A key to developing a diverse workforce is establishing a diverse student population in health professions programs. Objective: To examine the diversity of students in Doctor of Medicine (MD), Doctor of Osteopathic Medicine (DO), Doctor of Dental Surgery (DDS), Doctor of Dental Medicine (DMD), and Doctor of Pharmacy (PharmD) programs with emphasis on the trends of underrepresented minoritized groups (American Indian or Alaska Native, Black or African American, Hispanic or Latino, and Native Hawaiian or Other Pacific Islander) and sex relative to the overall age-adjusted US population. Design, Setting, and Participants: This cross-sectional study used deidentified, self-reported data from 2003 to 2019 from the Association of American Medical Colleges, American Association of Colleges of Osteopathic Medicine, American Dental Education Association, American Dental Association, and American Association of Colleges of Pharmacy. Data analysis was performed from 2003 to 2004 and from 2018 to 2019. Exposures: Data on the race, ethnicity, and sex of applicants, matriculants, and degrees conferred by health professions programs were collected and compared with the age-adjusted population in the US Census (aged 20-34 years) over time. Main Outcomes and Measures: The main outcomes were trends in the proportions of underrepresented minoritized groups and sex diversity among applicants, matriculants, and degrees conferred relative to the overall age-adjusted US population. Trends were measured using the representation quotient, which is defined as the ratio of the proportion of each subgroup to the total population of applicants, matriculants, or graduates relative to the proportion for that subgroup within the US Census population of similar age. Regression analysis was used to evaluate the trend over time. Results: A total of 594 352 applicants were analyzed across the examined programs. From 2003 to 2019, the proportions of individuals from underrepresented groups increased for DDS and DMD (applicants, from 1003 of 8176 to 1962 of 11 298 [5.1%]; matriculants, from 510 of 4528 to 966 of 6163 [4.2%]; degrees awarded, from 484 of 4350 to 878 of 6340 [2.7%]), PharmD (applicants, from 9045 of 71 966 to 11 653 of 50 482 [9.0%]; matriculants, from 5979 of 42 627 to 10 129 to 62 504 [6.3%]; degrees awarded, from 922 of 7770 to 2190 of 14 800 [3.0%]), and DO (applicants, from 740 of 6814 to 3478 of 21 090 [5.4%]; degrees awarded, 199 of 2713 to 582 of 6703 [1.4%]) programs, but decreased for MD programs (applicants, from 6066 of 34 791 to 7889 of 52 777 [-2.3%]; matriculants, 2506 of 16 541 to 2952 of 21 622 [-2.4%]; degrees awarded, from 2167 of 15 829 to 2349 of 19 937 [-0.1%]). Compared with age-adjusted US Census data, all programs had more Asian students and fewer male, American Indian or Alaska Native, Black or African American, Hispanic or Latino, and Native Hawaiian or Other Pacific Islander students (representation quotient <1). Conclusions and Relevance: In this cross-sectional study, most of the health professions in the study saw increases in underrepresented minority applicants, matriculants, and degrees conferred from 2003 to 2019; however, all programs were below the age-adjusted US Census data. The increased racial, ethnic, and sex diversity in the programs illustrates progress, but additional strategies are needed to achieve a more representative health care workforce.

P2Y purinergic signaling in prostate cancer: Emerging insights into pathophysiology and therapy.

Despite recent advances in the treatment landscape for prostate cancer, many challenges still remain. A more profound understanding of prostate cancer pathogenesis and the underlying mechanisms is critical to developing novel therapeutics strategies. Extracellular nucleotides play a central role in the growth and progression of a variety of cancer types - almost all tumor cells and immune cells express purinergic membrane receptors for extracellular nucleotides (ATP, ADP, UTP, UDP, UDP-sugar) and their metabolic nucleoside products (e.g., adenosine). Herein we review the pathological and immunomodulatory roles of P2Y purinergic nucleotide receptors in prostate cancer and their potential as therapeutic targets to address some of the clinical limitations in prostate cancer treatment.

Blending team-based learning and game-based learning in pharmacy education.

BACKGROUND AND PURPOSE: Team-based learning (TBL) and game-based learning (GBL) are evidence-based active learning pedagogies. This study reports a learning experience that harnesses TBL and GBL benefits by blending both pedagogies (referred herein as TGL) in the facilitation of an immunology module for pharmacy students. The manuscript presents the rationale for using TGL, a description of the TGL process, student outcomes and satisfaction with the learning experience, and TGL applicability in different topics/disciplines. EDUCATIONAL ACTIVITY AND SETTING: Sixty-five students were divided into 12 teams. Pre-class foundational readiness material was posted one week before class. Student readiness was assessed via individual and team readiness assurance tests (iRAT/tRAT) mapped to learning objectives, with immediate instructor-mediated debrief. Then student teams worked toward solving clinical applications using evidence-based clinical information databases, e.g., UpToDate, Lexicomp. Finally, students were engaged in a competitive online game designed to review topic's key concepts and evaluate student knowledge individually post-learning experience. FINDINGS: TGL process fulfilled learning outcomes, indicated by successful student performance in module-related assessments: iRAT = 92.5% ± 1.2; tRAT = 98.3% ± 1.1; educational game = 71.5% ± 3.6; block exam = 82.1% ± 5.3. Student survey indicated that >90% of students are satisfied with readiness material, alignment of activities with learning outcomes, engagement in active learning, gaining new relevant knowledge/skills/mindset, and merging TBL with GBL. SUMMARY: Combining GBL with TBL allowed assessing student performance individually after the learning experience, an element that is not part of canonical TBL structure, to ensure students are prepared for high-stake/board exams. TGL can be applied in diverse topics/disciplines and is generalizable to small and large cohorts.

SARS-CoV-2 early infection signature identified potential key infection mechanisms and drug targets.

BACKGROUND: The ongoing COVID-19 outbreak has caused devastating mortality and posed a significant threat to public health worldwide. Despite the severity of this illness and 2.3 million worldwide deaths, the disease mechanism is mostly unknown. Previous studies that characterized differential gene expression due to SARS-CoV-2 infection lacked robust validation. Although vaccines are  now available, effective treatment options are still out of reach. RESULTS: To characterize the transcriptional activity of SARS-CoV-2 infection, a gene signature consisting of 25 genes was generated using a publicly available RNA-Sequencing (RNA-Seq) dataset of cultured cells infected with SARS-CoV-2. The signature estimated infection level accurately in bronchoalveolar lavage fluid (BALF) cells and peripheral blood mononuclear cells (PBMCs) from healthy and infected patients (mean 0.001 vs. 0.958; P < 0.0001). These signature genes were investigated in their ability to distinguish the severity of SARS-CoV-2 infection in a single-cell RNA-Sequencing dataset. TNFAIP3, PPP1R15A, NFKBIA, and IFIT2 had shown bimodal gene expression in various immune cells from severely infected patients compared to healthy or moderate infection cases. Finally, this signature was assessed using the publicly available ConnectivityMap database to identify potential disease mechanisms and drug repurposing candidates. Pharmacological classes of tricyclic antidepressants, SRC-inhibitors, HDAC inhibitors, MEK inhibitors, and drugs such as atorvastatin, ibuprofen, and ketoconazole showed strong negative associations (connectivity score < - 90), highlighting the need for further evaluation of these candidates for their efficacy in treating SARS-CoV-2 infection. CONCLUSIONS: Thus, using the 25-gene SARS-CoV-2 infection signature, the SARS-CoV-2 infection status was captured in BALF cells, PBMCs and postmortem lung biopsies. In addition, candidate SARS-CoV-2 therapies with known safety profiles were identified. The signature genes could potentially also be used to characterize the COVID-19 disease severity in patients' expression profiles of BALF cells.

Pim1 maintains telomere length in mouse cardiomyocytes by inhibiting TGFß signalling.

AIMS: Telomere attrition in cardiomyocytes is associated with decreased contractility, cellular senescence, and up-regulation of proapoptotic transcription factors. Pim1 is a cardioprotective kinase that antagonizes the aging phenotype of cardiomyocytes and delays cellular senescence by maintaining telomere length, but the mechanism remains unknown. Another pathway responsible for regulating telomere length is the transforming growth factor beta (TGFß) signalling pathway where inhibiting TGFß signalling maintains telomere length. The relationship between Pim1 and TGFß has not been explored. This study delineates the mechanism of telomere length regulation by the interplay between Pim1 and components of TGFß signalling pathways in proliferating A549 cells and post-mitotic cardiomyocytes. METHODS AND RESULTS: Telomere length was maintained by lentiviral-mediated overexpression of PIM1 and inhibition of TGFß signalling in A549 cells. Telomere length maintenance was further demonstrated in isolated cardiomyocytes from mice with cardiac-specific overexpression of PIM1 and by pharmacological inhibition of TGFß signalling. Mechanistically, Pim1 inhibited phosphorylation of Smad2, preventing its translocation into the nucleus and repressing expression of TGFß pathway genes. CONCLUSION: Pim1 maintains telomere lengths in cardiomyocytes by inhibiting phosphorylation of the TGFß pathway downstream effectors Smad2 and Smad3, which prevents repression of telomerase reverse transcriptase. Findings from this study demonstrate a novel mechanism of telomere length maintenance and provide a potential target for preserving cardiac function.

Enhancing nutrition and lifestyle education for healthcare professional students through an interprofessional, team-based training program.

BACKGROUND AND PURPOSE: Nutrition and lifestyle modifications are effective interventions in tackling many chronic diseases, including cardiovascular diseases. However, healthcare professionals are not sufficiently trained in nutrition and lifestyle education. To address this gap, we established an interprofessional, team-based framework to train healthcare professional students on healthy nutrition and culturally competent dietary coaching and motivational interviewing. EDUCATIONAL ACTIVITY AND SETTING: Twelve doctor of pharmacy students from California Health Sciences University and three dietetic students from California State University, Fresno enrolled in this training program. Three pre-/post-surveys and one post-reflection worksheet were utilized to assess progress in student learning, including knowledge about obesity, confidence in coaching/mentoring families, perception of healthy nutrition, dietary habits, and interprofessional collaborative competencies. FINDINGS: Quantitative data and reflection worksheet thematic analysis revealed improvement in learner outcomes in the majority of the assessed areas. Students' knowledge about obesity and mentoring skills improved by 32%, knowledge about program curriculum improved by 167%, dietary habits improved by 28% and interprofessional competencies improved by 9%-34%. Thematic analysis of interprofessional educational reflection worksheets indicated positive reaction to the program, enhanced interprofessional outcomes, and potential application of acquired knowledge and skills on family and future patients. SUMMARY: Success of this interprofessional, team-based study encourages expanding the program to enroll more students from various healthcare specialties, including medical and nursing. This framework can be easily adapted by other healthcare programs to prepare healthcare providers to work interprofessionally and effectively include basic nutrition and lifestyle recommendations in disease management and preventive care.

Hypoxia Prevents Mitochondrial Dysfunction and Senescence in Human c-Kit+ Cardiac Progenitor Cells.

Senescence-associated dysfunction deleteriously affects biological activities of human c-Kit+ cardiac progenitor cells (hCPCs), particularly under conditions of in vitro culture. In comparison, preservation of self-renewal and decreases in mitochondrial reactive oxygen species (ROS) are characteristics of murine CPCs in vivo that reside within hypoxic niches. Recapitulating hypoxic niche oxygen tension conditions of ∼1% O2 in vitro for expansion of hCPCs rather than typical normoxic cell culture conditions (21% O2 ) could provide significant improvement of functional and biological activities of hCPCs. hCPCs were isolated and expanded under permanent hypoxic (hCPC-1%) or normoxic (hCPC-21%) conditions from left ventricular tissue explants collected during left ventricular assist device implantation. hCPC-1% exhibit increased self-renewal and suppression of senescence characteristics relative to hCPC-21%. Oxidative stress contributed to higher susceptibility to apoptosis, as well as decreased mitochondrial function in hCPC-21%. Hypoxia prevented accumulation of dysfunctional mitochondria, supporting higher oxygen consumption rates and mitochondrial membrane potential. Mitochondrial ROS was an upstream mediator of senescence since treatment of hCPC-1% with mitochondrial inhibitor antimycin A recapitulated mitochondrial dysfunction and senescence observed in hCPC-21%. NAD+ /NADH ratio and autophagic flux, which are key factors for mitochondrial function, were higher in hCPC-1%, but hCPC-21% were highly dependent on BNIP3/NIX-mediated mitophagy to maintain mitochondrial function. Overall, results demonstrate that supraphysiological oxygen tension during in vitro expansion initiates a downward spiral of oxidative stress, mitochondrial dysfunction, and cellular energy imbalance culminating in early proliferation arrest of hCPCs. Senescence is inhibited by preventing ROS through hypoxic culture of hCPCs. Stem Cells 2019;37:555-567.

Cardiac c-Kit Biology Revealed by Inducible Transgenesis.

RATIONALE: Biological significance of c-Kit as a cardiac stem cell marker and role(s) of c-Kit+ cells in myocardial development or response to pathological injury remain unresolved because of varied and discrepant findings. Alternative experimental models are required to contextualize and reconcile discordant published observations of cardiac c-Kit myocardial biology and provide meaningful insights regarding clinical relevance of c-Kit signaling for translational cell therapy. OBJECTIVE: The main objectives of this study are as follows: demonstrating c-Kit myocardial biology through combined studies of both human and murine cardiac cells; advancing understanding of c-Kit myocardial biology through creation and characterization of a novel, inducible transgenic c-Kit reporter mouse model that overcomes limitations inherent to knock-in reporter models; and providing perspective to reconcile disparate viewpoints on c-Kit biology in the myocardium. METHODS AND RESULTS: In vitro studies confirm a critical role for c-Kit signaling in both cardiomyocytes and cardiac stem cells. Activation of c-Kit receptor promotes cell survival and proliferation in stem cells and cardiomyocytes of either human or murine origin. For creation of the mouse model, the cloned mouse c-Kit promoter drives Histone2B-EGFP (enhanced green fluorescent protein; H2BEGFP) expression in a doxycycline-inducible transgenic reporter line. The combination of c-Kit transgenesis coupled to H2BEGFP readout provides sensitive, specific, inducible, and persistent tracking of c-Kit promoter activation. Tagging efficiency for EGFP+/c-Kit+ cells is similar between our transgenic versus a c-Kit knock-in mouse line, but frequency of c-Kit+ cells in cardiac tissue from the knock-in model is 55% lower than that from our transgenic line. The c-Kit transgenic reporter model reveals intimate association of c-Kit expression with adult myocardial biology. Both cardiac stem cells and a subpopulation of cardiomyocytes express c-Kit in uninjured adult heart, upregulating c-Kit expression in response to pathological stress. CONCLUSIONS: c-Kit myocardial biology is more complex and varied than previously appreciated or documented, demonstrating validity in multiple points of coexisting yet heretofore seemingly irreconcilable published findings.

Empowering human cardiac progenitor cells by P2Y14 nucleotide receptor overexpression.

KEY POINTS: Autologous cardiac progenitor cell (CPC) therapy is a promising approach for treatment of heart failure (HF). There is an unmet need to identify inherent deficits in aged/diseased human CPCs (hCPCs) derived from HF patients in the attempts to augment their regenerative capacity prior to use in the clinical setting. Here we report significant functional correlations between phenotypic properties of hCPCs isolated from cardiac biopsies of HF patients, clinical parameters of patients and expression of the P2Y14 purinergic receptor (P2Y14 R), a crucial detector for extracellular UDP-sugars released during injury/stress. P2Y14 R is downregulated in hCPCs derived from HF patients with lower ejection fraction or diagnosed with diabetes. Augmenting P2Y14 R expression levels in aged/diseased hCPCs antagonizes senescence and improves functional responses. This study introduces purinergic signalling modulation as a potential strategy to rejuvenate and improve phenotypic characteristics of aged/functionally compromised hCPCs prior to transplantation in HF patients. ABSTRACT: Autologous cardiac progenitor cell therapy is a promising alternative approach to current inefficient therapies for heart failure (HF). However, ex vivo expansion and pharmacological/genetic modification of human cardiac progenitor cells (hCPCs) are necessary interventions to rejuvenate aged/diseased cells and improve their regenerative capacities. This study was designed to assess the potential of improving hCPC functional capacity by targeting the P2Y14 purinergic receptor (P2Y14 R), which has been previously reported to induce regenerative and anti-senescence responses in a variety of experimental models. c-Kit+ hCPCs were isolated from cardiac biopsies of multiple HF patients undergoing left ventricular assist device implantation surgery. Significant correlations existed between the expression of P2Y14 R in hCPCs and clinical parameters of HF patients. P2Y14 R was downregulated in hCPCs derived from patients with a relatively lower ejection fraction and patients diagnosed with diabetes. hCPC lines with lower P2Y14 R expression did not respond to P2Y14 R agonist UDP-glucose (UDP-Glu) while hCPCs with higher P2Y14 R expression showed enhanced proliferation in response to UDP-Glu stimulation. Mechanistically, UDP-Glu stimulation enhanced the activation of canonical growth signalling pathways ERK1/2 and AKT. Restoring P2Y14 R expression levels in functionally compromised hCPCs via lentiviral-mediated overexpression improved proliferation, migration and survival under stress stimuli. Additionally, P2Y14 R overexpression reversed senescence-associated morphology and reduced levels of molecular markers of senescence p16INK4a , p53, p21 and mitochondrial reactive oxygen species. Findings from this study unveil novel biological roles of the UDP-sugar receptor P2Y14 in hCPCs and suggest purinergic signalling modulation as a promising strategy to improve phenotypic properties of functionally impaired hCPCs.

P2Y2 Nucleotide Receptor Prompts Human Cardiac Progenitor Cell Activation by Modulating Hippo Signaling.

RATIONALE: Autologous stem cell therapy using human c-Kit+ cardiac progenitor cells (hCPCs) is a promising therapeutic approach for treatment of heart failure (HF). However, hCPCs derived from aged patients with HF with genetic predispositions and comorbidities of chronic diseases exhibit poor proliferative and migratory capabilities, which impair overall reparative potential for injured myocardium. Therefore, empowering functionally compromised hCPCs with proregenerative molecules ex vivo is crucial for improving the therapeutic outcome in patients with HF. OBJECTIVE: To improve hCPC proliferation and migration responses that are critical for regeneration by targeting proregenerative P2Y2 nucleotide receptor (P2Y2R) activated by extracellular ATP and UTP molecules released following injury/stress. METHODS AND RESULTS: c-Kit+ hCPCs were isolated from cardiac tissue of patients with HF undergoing left ventricular assist device implantation surgery. Correlations between P2 nucleotide receptor expression and hCPC growth kinetics revealed downregulation of select P2 receptors, including P2Y2R, in slow-growing hCPCs compared with fast growers. hCPC proliferation and migration significantly improved by overexpressing or stimulating P2Y2R. Mechanistically, P2Y2R-induced proliferation and migration were dependent on activation of YAP (yes-associated protein)-the downstream effector of Hippo signaling pathway. CONCLUSIONS: Proliferation and migration of functionally impaired hCPCs are enhanced by P2Y2R-mediated YAP activation, revealing a novel link between extracellular nucleotides released during injury/stress and Hippo signaling-a central regulator of cardiac regeneration. Functional correlations exist between hCPC phenotypic properties and P2 purinergic receptor expression. Lack of P2Y2R and other crucial purinergic stress detectors could compromise hCPC responsiveness to presence of extracellular stress signals. These findings set the stage for subsequent studies to assess purinergic signaling modulation as a potential strategy to improve therapeutic outcome for use of hCPCs in patients with HF.

Inflammation and Epithelial-Mesenchymal Transition in Pancreatic Ductal Adenocarcinoma: Fighting Against Multiple Opponents.

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and one of the most lethal human cancers. Inflammation is a critical component in PDAC initiation and progression. Inflammation also contributes to the aggressiveness of PDAC indirectly via induction of epithelial-mesenchymal transition (EMT), altogether leading to enhanced resistance to chemotherapy and poor survival rates. This review gives an overview of the key pro-inflammatory signaling pathways involved in PDAC pathogenesis and discusses the role of inflammation in induction of EMT and development of chemoresistance in patients with PDAC.

Concurrent Isolation of 3 Distinct Cardiac Stem Cell Populations From a Single Human Heart Biopsy.

RATIONALE: The relative actions and synergism between distinct myocardial-derived stem cell populations remain obscure. Ongoing debates on optimal cell population(s) for treatment of heart failure prompted implementation of a protocol for isolation of multiple stem cell populations from a single myocardial tissue sample to develop new insights for achieving myocardial regeneration. OBJECTIVE: Establish a robust cardiac stem cell isolation and culture protocol to consistently generate 3 distinct stem cell populations from a single human heart biopsy. METHODS AND RESULTS: Isolation of 3 endogenous cardiac stem cell populations was performed from human heart samples routinely discarded during implantation of a left ventricular assist device. Tissue explants were mechanically minced into 1 mm3 pieces to minimize time exposure to collagenase digestion and preserve cell viability. Centrifugation removes large cardiomyocytes and tissue debris producing a single cell suspension that is sorted using magnetic-activated cell sorting technology. Initial sorting is based on tyrosine-protein kinase Kit (c-Kit) expression that enriches for 2 c-Kit+ cell populations yielding a mixture of cardiac progenitor cells and endothelial progenitor cells. Flowthrough c-Kit- mesenchymal stem cells are positively selected by surface expression of markers CD90 and CD105. After 1 week of culture, the c-Kit+ population is further enriched by selection for a CD133+ endothelial progenitor cell population. Persistence of respective cell surface markers in vitro is confirmed both by flow cytometry and immunocytochemistry. CONCLUSIONS: Three distinct cardiac cell populations with individualized phenotypic properties consistent with cardiac progenitor cells, endothelial progenitor cells, and mesenchymal stem cells can be successfully concurrently isolated and expanded from a single tissue sample derived from human heart failure patients.

S100A4 protects the myocardium against ischemic stress.

BACKGROUND: Myocardial infarction is followed by cardiac dysfunction, cellular death, and ventricular remodeling, including tissue fibrosis. S100A4 protein plays multiple roles in cellular survival, and tissue fibrosis, but the relative role of the S100A4 in the myocardium after myocardial infarction is unknown. This study aims to investigate the role of S100A4 in myocardial remodeling and cardiac function following infarct damage. METHODS AND RESULTS: S100A4 expression is low in the adult myocardium, but significantly increased following myocardial infarction. Deletion of S100A4 increased cardiac damage after myocardial infarction, whereas cardiac myocyte-specific overexpression of S100A4 protected the infarcted myocardium. Decreased cardiac function in S100A4 Knockout mice was accompanied with increased cardiac remodeling, fibrosis, and diminished capillary density in the remote myocardium. Loss of S100A4 caused increased apoptotic cell death both in vitro and in vivo in part mediated by decreased VEGF expression. Conversely, S100A4 overexpression protected cells against apoptosis in vitro and in vivo. Increased pro-survival AKT-signaling explained reduced apoptosis in S100A4 overexpressing cells. CONCLUSION: S100A4 expression protects cardiac myocytes against myocardial ischemia and is required for stabilization of cardiac function after MI.