Cell and gene therapy workforce development: the role of the International Society for Cell & Gene Therapy (ISCT) in the creation of a sustainable and skilled workforce in Europe

Advanced therapy medicinal products; Career development; TrainingMedicamentos de terapia avanzada; Desarrollo profesional; FormaciónMedicaments de teràpia avançada; Desenvolupament professional; FormacióThe development and production of cell gene and tissue (CGT)-based therapies requires a specialized workforce. Entering the CGT arena is complex because it involves different scientific and biomedical aspects (e.g., immunology, stem cell biology and transplantation), as well as knowledge of regulatory affairs and compliance with pharmaceutical quality standards. Currently, both industry and academia are facing a worldwide workforce shortage, whereas only a handful of educational and training initiatives specifically address the peculiarities of CGT product development, the procurement of substances of human origin, the manufacturing process itself and clinical monitoring and biovigilance. The training offered by traditional Master's and PhD programs is not suited for training a skilled workforce ready to enter the increasingly fast-growing CGT field. Indeed, typically these programs are of long duration and only partially cover the required competencies, whereas the demand for a specialized workforce relentlessly increases. In this paper, we (i) present and discuss our understanding of the roots of current growth acceleration of the CGT field; (ii) anticipate future workforce needs due to the expected increase of marketed CGT-based therapies and (iii) evaluate potential solutions that seek to adapt, develop and implement current educational and training initiatives. Importantly for these solutions, we call for scientific societies, such as the International Society for Cell & Gene Therapy, to play a more active role and act as catalysers for new initiatives, building bridges between academia and Industry to establish effective educational and training programs that will engage and prepare a new generation of qualified professionals for entry into the CGT field

Paracrine mechanisms of stem cell reparative and regenerative actions in the heart

Stem cells play an important role in restoring cardiac function in the damaged heart. In order to mediate repair, stem cells need to replace injured tissue by differentiating into specialized cardiac cell lineages and/or manipulating the cell and molecular mechanisms governing repair. Despite early reports describing engraftment and successful regeneration of cardiac tissue in animal models of heart failure, these events appear to be infrequent and yield too few new cardiomyocytes to account for the degree of improved cardiac function observed. Instead, mounting evidence suggests that stem cell mediated repair takes place via the release of paracrine factors into the surrounding tissue that subsequently direct a number of restorative processes including myocardial protection, neovascularization, cardiac remodeling, and differentiation. The potential for diverse stem cell populations to moderate many of the same processes as well as key paracrine factors and molecular pathways involved in stem cell-mediated cardiac repair will be discussed in this review. This article is part of a special issue entitled, "Cardiovascular Stem Cells Revisited"

Generation of two human induced pluripotent stem cell (hiPSC) lines from a long QT syndrome South African founder population.

Abstract We generated PSMi001-A and PSMi008-A hiPSC lines from two individuals belonging to a South African (SA) founder population in which the malignant KCNQ1-A341V mutation cosegregates with the Long QT Syndrome (LQTS) phenotype. PSMi001-A was derived from an asymptomatic KCNQ1-A341V mutation carrier, whereas PSMi008-A was derived from a healthy non-mutation carrier, heterozygous for the minor variant rs16847548 on the NOS1AP gene, associated with QT prolongation in the general population, and with a greater risk for cardiac arrest in the affected members of the SA founder population. The hiPSCs, generated using the Yamanaka's retroviruses, display pluripotent stem cell features and trilineage differentiation potential

Direct oral Xa inhibitors versus warfarin in patients with cancer and atrial fibrillation: a meta-analysis

Patients with cancer are at higher risk of atrial fibrillation, thromboembolic complications and bleeding events compared with the general population. The aim of the present meta-analysis was to compare the efficacy and safety of direct oral Xa inhibitor anticoagulants versus warfarin in patients with cancer and atrial fibrillation

Secreted frizzled related protein 2 (Sfrp2) is the key Akt-mesenchymal stem cell-released paracrine factor mediating myocardial survival and repair

Stem cell therapy has emerged as a promising tool for the treatment of a variety of diseases. Previously, we have shown that Akt-modified mesenchymal stem cells mediate tissue repair through paracrine mechanisms. Using a comprehensive functional genomic strategy, we show that secreted frizzled related protein 2 (Sfrp2) is the key stem cell paracrine factor that mediates myocardial survival and repair after ischemic injury. Sfrp2 is known to modulate Wnt signaling, and we demonstrate that cardiomyocytes treated with secreted frizzled related protein increase cellular beta-catenin and up-regulate expression of antiapoptotic genes. These findings reveal the key role played by Sfrp2 in mediating the paracrine effects of Akt-mesenchymal stem cells on tissue repair and identify modulation of Wnt signaling as a therapeutic target for heart disease

Generation of the human induced pluripotent stem cell (hiPSC) line PSMi003-A from a patient affected by an autosomal recessive form of Long QT Syndrome type 1

Abstract We generated human induced pluripotent stem cells (hiPSCs) from dermal fibroblasts of a 51 years old female patient homozygous for the mutation c.535 G>A p.G179S on the KCNQ1 gene, causing a severe form of autosomal recessive Long QT Syndrome type 1 (AR-LQT1), not associated with deafness. The hiPSCs, generated using four retroviruses each encoding for a reprogramming factor OCT4, SOX2, KLF4, cMYC, are pluripotent and can differentiate into spontaneously beating cardiomyocytes (hiPSC-CMs)

Generation of the human induced pluripotent stem cell (hiPSC) line PSMi006-A from a patient affected by an autosomal recessive form of Long QT Syndrome type 1

We generated human induced pluripotent stem cells (hiPSCs) from dermal fibroblasts of a 40 years old female patient homozygous for the mutation c.535 G > A p.G179S on the KCNQ1 gene, causing a severe form of autosomal recessive Long QT Syndrome type 1 (AR-LQT1). The hiPSCs, generated using classical approach of the four retroviruses enconding the reprogramming factors OCT4, SOX2, cMYC and KLF4, display pluripotent stem cell characteristics, and differentiate into cell lineages of all three germ layers: endoderm, mesoderm and ectoderm. Keywords: Endoderm, Mesoderm, Ectoder

NOS1AP polymorphisms reduce NOS1 activity and interact with prolonged repolarization in arrhythmogenesis

Aims  NOS1AP single-nucleotide polymorphisms (SNPs) correlate with QT prolongation and cardiac sudden death in patients affected by long QT syndrome type 1 (LQT1). NOS1AP targets NOS1 to intracellular effectors. We hypothesize that NOS1AP SNPs cause NOS1 dysfunction and this may converge with prolonged action-potential duration (APD) to facilitate arrhythmias. Here we test (i) the effects of NOS1 inhibition and their interaction with prolonged APD in a guinea pig cardiomyocyte (GP-CMs) LQT1 model; (ii) whether pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from LQT1 patients differing for NOS1AP variants and mutation penetrance display a phenotype compatible with NOS1 deficiency. Methods and results  In GP-CMs, NOS1 was inhibited by S-Methyl-L-thiocitrulline acetate (SMTC) or Vinyl-L-NIO hydrochloride (L-VNIO); LQT1 was mimicked by IKs blockade (JNJ303) and β-adrenergic stimulation (isoproterenol). hiPSC-CMs were obtained from symptomatic (S) and asymptomatic (AS) KCNQ1-A341V carriers, harbouring the minor and major alleles of NOS1AP SNPs (rs16847548 and rs4657139), respectively. In GP-CMs, NOS1 inhibition prolonged APD, enhanced ICaL and INaL, slowed Ca2+ decay, and induced delayed afterdepolarizations. Under action-potential clamp, switching to shorter APD suppressed ‘transient inward current’ events induced by NOS1 inhibition and reduced cytosolic Ca2+. In S (vs. AS) hiPSC-CMs, APD was longer and ICaL larger; NOS1AP and NOS1 expression and co-localization were decreased. Conclusion  The minor NOS1AP alleles are associated with NOS1 loss of function. The latter likely contributes to APD prolongation in LQT1 and converges with it to perturb Ca2+ handling. This establishes a mechanistic link between NOS1AP SNPs and aggravation of the arrhythmia phenotype in prolonged repolarization syndromes

Smoker's paradox in ST-elevation myocardial infarction: Role of inflammation and platelets.

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