Human Induced Pluripotent Stem Cells as a Disease Model System for Heart Failure

Purpose of review!#!Heart failure is among the most prevalent disease complexes overall and is associated with high morbidity and mortality. The underlying aetiology is manifold including coronary artery disease, genetic alterations and mutations, viral infections, adverse immune responses, and cardiac toxicity. To date, no specific therapies have been developed despite notable efforts. This can especially be attributed to hurdles in translational research, mainly due to the lack of proficient models of heart failure limited translation of therapeutic approaches from bench to bedside.!##!Recent findings!#!Human induced pluripotent stem cells (hiPSCs) are rising in popularity, granting the ability to divide infinitely, to hold human, patient-specific genome, and to differentiate into any human cell, including cardiomyocytes (hiPSC-CMs). This brings magnificent promise to cardiological research, providing the possibility to recapitulate cardiac diseases in a dish. Advances in yield, maturity, and in vivo resemblance due to straightforward, low-cost protocols, high-throughput approaches, and complex 3D cultures have made this tool widely applicable. In recent years, hiPSC-CMs have been used to model a wide variety of cardiac diseases, bringing along the possibility to not only elucidate molecular mechanisms but also to test novel therapeutic approaches in the dish. Within the last decade, hiPSC-CMs have been exponentially employed to model heart failure. Constant advancements are aiming at improvements of differentiation protocols, hiPSC-CM maturity, and assays to elucidate molecular mechanisms and cellular functions. However, hiPSC-CMs are remaining relatively immature, and in vitro models can only partially recapitulate the complex interactions in vivo. Nevertheless, hiPSC-CMs have evolved as an essential model system in cardiovascular research

Human Induced Pluripotent Stem Cells as a Disease Model System for Heart Failure

Abstract Purpose of Review Heart failure is among the most prevalent disease complexes overall and is associated with high morbidity and mortality. The underlying aetiology is manifold including coronary artery disease, genetic alterations and mutations, viral infections, adverse immune responses, and cardiac toxicity. To date, no specific therapies have been developed despite notable efforts. This can especially be attributed to hurdles in translational research, mainly due to the lack of proficient models of heart failure limited translation of therapeutic approaches from bench to bedside. Recent Findings Human induced pluripotent stem cells (hiPSCs) are rising in popularity, granting the ability to divide infinitely, to hold human, patient-specific genome, and to differentiate into any human cell, including cardiomyocytes (hiPSC-CMs). This brings magnificent promise to cardiological research, providing the possibility to recapitulate cardiac diseases in a dish. Advances in yield, maturity, and in vivo resemblance due to straightforward, low-cost protocols, high-throughput approaches, and complex 3D cultures have made this tool widely applicable. In recent years, hiPSC-CMs have been used to model a wide variety of cardiac diseases, bringing along the possibility to not only elucidate molecular mechanisms but also to test novel therapeutic approaches in the dish. Summary Within the last decade, hiPSC-CMs have been exponentially employed to model heart failure. Constant advancements are aiming at improvements of differentiation protocols, hiPSC-CM maturity, and assays to elucidate molecular mechanisms and cellular functions. However, hiPSC-CMs are remaining relatively immature, and in vitro models can only partially recapitulate the complex interactions in vivo. Nevertheless, hiPSC-CMs have evolved as an essential model system in cardiovascular research. </jats:sec

MicroRNAs in cardiovascular ageing

MicroRNAs (miRs) have emerged as potent regulators of pathways in physiological and disease contexts. This review focuses on the role of miRs in ageing of the cardiovascular system. Several miRs have been described to be regulated during ageing and some of these miRs are involved in the regulation of ageing-related processes. We discuss the roles of miR-34, miR-217 and miR-29, which are induced during ageing in the vasculature. The roles of miR-34, miR-29 (age-induced) and miR-18/19, which are decreased during ageing in the heart, are discussed as well. Furthermore, numerous miRs that play a role in diseases associated with ageing, like diabetes, atherosclerosis, hypertension, cardiac hypertrophy and atrial fibrillation, are also briefly discussed. miRs also serve as circulating biomarkers for cardiovascular ageing or ageing-associated diseases. Finally, pharmacological modulation of ageing-related miRs might become a promising strategy to combat cardiovascular ageing in a clinical setting

Highly Efficient Peripheral Blood Progenitor Cell Mobilization in Myeloma Patients by Single-Dose Application of 12 mg Pegylated G-CSF.

Abstract Autologous peripheral blood stem cell (PBSC) transplantation leads to significant prolongation of survival in patients with different malignancies. For PBSC mobilization a combination of myelosuppressive chemotherapy and granulocyte colony stimulating factor (G-CSF) are administered. The optimal application of G-CSF is twice daily. New G-CSF formulations with prolonged half-life carry the promise of reduced patient strain, increased compliance and via continuously high G-CSF serum levels possibly improved PBSC mobilization. We initiated a study with pegfilgrastim-supported mobilization chemotherapy in stage II and III myeloma patients. Patients received up-front treatment with three cycles of vincristin, doxorubicin, dexamethason (VAD) or thalidomide, doxorubicin, dexamethason (TAD). The mobilization regime consisted of four days chemotherapy with cyclophosphamide 1g/m2 day1, doxorubicin 15mg/m2 day 1–4, dexamethason 40 mg d 1–4 p.o. (CAD) and a single administration of 12 mg pegfilgrastim subcutaneously on day five. 25 patients (median age 57, 12 female, 13 male) received pegfilgrastim and leukapheresis was started 6–17 days (mean 10 days) after treatment with a range of maximum CD34 cell count between 7,2 and 842 (mean: 119) CD34+ cells/μl peripheral blood. After leukapheresis 6.2 * 10e6 to 40.5 * 10e6 (mean 13.8 *10e6) CD34+ cells per kilogram body weight were collected. 11 patients achieved the target number of 7.5 * 10e6 CD34+ cells per kilogram body weight during a single apheresis, while 5 patients needed two, 7 patients needed three and 2 patients needed four apheresies on consecutive days. 3 patients required additional administration of filgrastim. 2 patients received 6 mg pegfilgrastim off study. Both achieved sufficient numbers of CD34+ cells (12.7 and 20.8 * 10e6 CD34+ per kg BW). There were only minimal adverse effects. Four patients reported of bone pain or nausea. Mobilization failures did not occur in this patient population. To date, 16 patients have been transplanted with a mean of 6,03* 10e6 CD34+ per kg BW (range 2,4 to 13,5). Reconstitution (reaching a leukocyte count of &amp;gt;1,0/nl) was reached within a mean of 13 days (range 11–21). On the basis of these first results we conclude that a single dose application of 12 mg pegfilgrastim after CAD treatment allows collection of more than 3 autografts in two or less apheresis session in the majority of myeloma patients. Reduction of apheresis sessions is a significant clinical cost-effectiveness end point in PBPC mobilization.</jats:p