Selection for CD26 and CD49A Cells From Pluripotent Stem Cells-Derived Islet-Like Clusters Improves Therapeutic Activity in Diabetic Mice.

Background: Cell therapy of diabetes aims at restoring the physiological control of blood glucose by transplantation of functional pancreatic islet cells. A potentially unlimited source of cells for such transplantations would be islet cells derived from an differentiation of human pluripotent stem cells (hESC/hiPSC). The islet-like clusters (ILC) produced by the known differentiation protocols contain various cell populations.

Derivation of Pericytes from Human Pluripotent Stem Cells.

Human pluripotent stem cells (hPSCs), either embryonic or induced, offer a plentiful platform for derivation of multiple cell types. Pericytes, generated from hPSCs, are multipotent precursors with vasculogenic features that exhibit high proliferation capability in long-term cultures. Administration of hPSC-pericytes into ischemic murine hind limb is associated with therapeutic angiogenesis and attenuation of muscle wasting.

Cardiac Fibroblast-Induced Pluripotent Stem Cell-Derived Exosomes as a Potential Therapeutic Mean for Heart Failure.

The limited regenerative capacity of the injured myocardium leads to remodeling and often heart failure. Novel therapeutic approaches are essential. Induced pluripotent stem cells (iPSC) differentiated into cardiomyocytes are a potential future therapeutics.

Safety and efficacy of human embryonic stem cell-derived astrocytes following intrathecal transplantation in SOD1 and NSG animal models.

Background: Amyotrophic lateral sclerosis (ALS) is a motor neuron (MN) disease characterized by the loss of MNs in the central nervous system. As MNs die, patients progressively lose their ability to control voluntary movements, become paralyzed and eventually die from respiratory/deglutition failure. Despite the selective MN death in ALS, there is growing evidence that malfunctional astrocytes play a crucial role in disease progression.

20th Anniversary of Isolation of Human Embryonic Stem Cells: A Personal Perspective.

Following Jamie Thomson's lecture on primate embryonic stem cells (ESCs) at a meeting I had organized in March 1997, in Israel, to celebrate receipt of the Wolf Prize in Agriculture to my colleague and friend Neal First, frozen human embryos donated for research in Israel were shipped to Wisconsin. The five hESC lines (H1, H7, H9, H13, and H14) were established by early 1998 and transferred to my laboratory just before publication of their existence in Science, on November 6, 1998. The distribution of the cells from my institute to several laboratories, as early as 1999, enhanced the development of hESC research worldwide.

Scalable Expansion of Pluripotent Stem Cells.

Large-scale expansion of pluripotent stem cells (PSC) in a robust, well-defined, and monitored process is essential for production of cell-based therapeutic products. The transition from laboratory-scale protocols to industrial-scale production is one of the first milestones to be achieved in order to use both human embryonic stem cells (ESC) and induced pluripotent stem cells (iPSC) as the starting material for cellular products. The methods to be developed require adjustment of the culture platforms, optimization of culture parameters, and adaptation of downstream procedures.

Functional abnormalities in iPSC-derived cardiomyocytes generated from CPVT1 and CPVT2 patients carrying ryanodine or calsequestrin mutations.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia characterized by syncope and sudden death occurring during exercise or acute emotion. CPVT is caused by abnormal intracellular Ca(2+) handling resulting from mutations in the RyR2 or CASQ2 genes. Because CASQ2 and RyR2 are involved in different aspects of the excitation-contraction coupling process, we hypothesized that these mutations are associated with different functional and intracellular Ca(²+) abnormalities.

Microbial-derived lithocholic acid and vitamin K2 drive the metabolic maturation of pluripotent stem cells-derived and fetal hepatocytes.

Unlabelled: The liver is the main organ responsible for the modification, clearance, and transformational toxicity of most xenobiotics owing to its abundance in cytochrome P450 (CYP450) enzymes. However, the scarcity and variability of primary hepatocytes currently limits their utility. Human pluripotent stem cells (hPSCs) represent an excellent source of differentiated hepatocytes; however, current protocols still produce fetal-like hepatocytes with limited mature function.

Glycolysis-mediated changes in acetyl-CoA and histone acetylation control the early differentiation of embryonic stem cells.

Loss of pluripotency is a gradual event whose initiating factors are largely unknown. Here we report the earliest metabolic changes induced during the first hours of differentiation. High-resolution NMR identified 44 metabolites and a distinct metabolic transition occurring during early differentiation.

Human embryonic stem cells vs human induced pluripotent stem cells for cardiac repair.

Human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) have the capacity to differentiate into any specialized cell type, including cardiomyocytes. Therefore, hESC-derived and hiPSC-derived cardiomyocytes (hESC-CMs and hiPSC-CMs, respectively) offer great potential for cardiac regenerative medicine. Unlike some organs, the heart has a limited ability to regenerate, and dysfunction resulting from significant cardiomyocyte loss under pathophysiological conditions, such as myocardial infarction (MI), can lead to heart failure.

Immunoevasive pericytes from human pluripotent stem cells preferentially modulate induction of allogeneic regulatory T cells.

Isolated microvessel-residing pericytes and pericytes from human pluripotent stem cells (hPSCs) exhibit mesenchymal stem cell-like characteristics and therapeutic properties. Despite growing interest in pericyte-based stem cell therapy, their immunogenicity and immunomodulatory effects on nonactivated T cells are still poorly defined, in particular those of vasculogenic hPSC pericytes. We found that tissue-embedded and unstimulated cultured hPSC- or tissue-derived pericytes constitutively expressed major histocompatibility complex (MHC) class I and the inhibitory programmed cell death-ligand 1/2 (PD-L1/2) molecules but not MHC class II or CD80/CD86 costimulatory molecules.

Human embryonic stem cells prevent T-cell activation by suppressing dendritic cells function via TGF-beta signaling pathway.

Human embryonic stem cells (hESCs) represent a potential source of transplantable cells for regenerative medicine, but development of teratoma even in syngenic recipients represents a critical obstacle to safe stem cell-based therapies. We hypothesized that hESCs escape the immune surveillance by regulating the environmental immune system. Using cocultures of hESCs with allogenic peripheral blood mononuclear cells, we demonstrated that hESCs prevent proliferation and activation of human CD4+ T lymphocytes, an effect dependent upon monocytes.

The generation of hybrid electrospun nanofiber layer with extracellular matrix derived from human pluripotent stem cells, for regenerative medicine applications.

Extracellular matrix (ECM) has been utilized as a biological scaffold for tissue engineering applications in a variety of body systems, due to its bioactivity and biocompatibility. In the current study we developed a modified protocol for the efficient and reproducible derivation of mesenchymal progenitor cells (MPCs) from human embryonic stem cells as well as human induced pluripotent stem cells (hiPSCs) originating from hair follicle keratinocytes (HFKTs). ECM was produced from these MPCs and characterized in comparison to adipose mesenchymal stem cell ECM, demonstrating robust ECM generation by the excised HFKT-iPSC-MPCs.

From beat rate variability in induced pluripotent stem cell-derived pacemaker cells to heart rate variability in human subjects.

Background: We previously reported that induced pluripotent stem cell-derived cardiomyocytes manifest beat rate variability (BRV) resembling heart rate variability (HRV) in the human sinoatrial node. We now hypothesized the BRV-HRV continuum originates in pacemaker cells.

Objective: To investigate whether cellular BRV is a source of HRV dynamics, we hypothesized 3 levels of interaction among different cardiomyocyte entities: (1) single pacemaker cells, (2) networks of electrically coupled pacemaker cells, and (3) the in situ sinoatrial node.

Three-dimensional transperineal ultrasound for imaging mesh implants following sacrocolpopexy.

Objective: To characterize, using three-dimensional (3D) transperineal ultrasound, the appearance, position and dimensions of mesh implants following minimally invasive abdominal sacrocolpopexy.

Methods: In women who underwent sacrocolpopexy, mesh was evaluated at rest and on maximal Valsalva, on all 3D orthogonal planes and rendered views. Mesh dimensions were obtained by 3D processing in the midsagittal and coronal planes (anterior, posterior and sacral arm) and were analyzed offline, the operator blinded to clinical data.

ADAR1 is involved in the regulation of reprogramming human fibroblasts to induced pluripotent stem cells.

Adenosine-to-inosine (A-to-I) RNA editing is a post-transcriptional, site-specific modification process that is catalyzed by Adenosine Deaminase Acting on RNA (ADAR) gene family members. Since ADARs act on double-stranded RNA, most A-to-I editing occurs within repetitive elements, particularly Alu elements, as the result of the inherent property of these sequences to fold and form double strands. ADAR1-mediated A-to-I RNA editing was recently implicated in the regulation of human embryonic stem cells (hESCs).

Modeling Catecholaminergic Polymorphic Ventricular Tachycardia using Induced Pluripotent Stem Cell-derived Cardiomyocytes.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic cardiac disorder characterized by life-threatening arrhythmias induced by physical or emotional stress, in the absence structural heart abnormalities. The arrhythmias may cause syncope or degenerate into cardiac arrest and sudden death which usually occurs during childhood. Recent studies have shown that CPVT is caused by mutations in the cardiac ryanodine receptor type 2 (RyR2) or calsequestrin 2 (CASQ2) genes.

Induced pluripotent stem cells (iPSCs) derived from different cell sources and their potential for regenerative and personalized medicine.

Human induced pluripotent stem cells (hiPSCs) have great potential as a robust source of progenitors for regenerative medicine. The novel technology also enables the derivation of patient-specific cells for applications to personalized medicine, such as for personal drug screening and toxicology. However, the biological characteristics of iPSCs are not yet fully understood and their similarity to human embryonic stem cells (hESCs) is still unresolved.

SK4 Ca2+ activated K+ channel is a critical player in cardiac pacemaker derived from human embryonic stem cells.

Proper expression and function of the cardiac pacemaker is a critical feature of heart physiology. Two main mechanisms have been proposed: (i) the "voltage-clock," where the hyperpolarization-activated funny current If causes diastolic depolarization that triggers action potential cycling; and (ii) the "Ca(2+) clock," where cyclical release of Ca(2+) from Ca(2+) stores depolarizes the membrane during diastole via activation of the Na(+)-Ca(2+) exchanger. Nonetheless, these mechanisms remain controversial.

Prophylactic maternal N-acetylcysteine in rats prevents maternal inflammation-induced offspring cerebral injury shown on magnetic resonance imaging.

Objective: Maternal infection or inflammation may induce fetal inflammatory responses associated with fetal injury and cerebral palsy. We sought to assess the inflammation-associated neuroprotective potential of prophylactic N-acetyl-cysteine (NAC). We examined the effect of NAC on prevention of maternal lipopolysaccharide (LPS)-induced neonatal brain injury using magnetic resonance imaging.

Therapeutic potential of perivascular cells from human pluripotent stem cells.

Vascularization of injured tissues or artificial grafts is a major challenge in tissue engineering, stimulating a continued search for alternative sources for vasculogenic cells and the development of therapeutic strategies. Human pluripotent stem cells (hPSCs), either embryonic or induced, offer a plentiful platform for the derivation of large numbers of vasculogenic cells, as required for clinical transplantations. Various protocols for generation of vasculogenic smooth muscle cells (SMCs) from hPSCs have been described with considerably different SMC derivatives.

Maternal lipopolysaccharide alters the newborn oxidative stress and C-reactive protein levels in response to an inflammatory stress.

Maternal infection is associated with oxidative stress (OS) and inflammatory responses. We have previously shown that maternal exposure to lipopolysaccharide (LPS) at E18 alters the subsequent offspring immune response. As immune responses are mediated, in part, by OS, we sought to determine if maternal inflammation during pregnancy programs offspring OS and C-reactive protein (CRP) levels.

Altered A-to-I RNA editing in human embryogenesis.

Post-transcriptional events play an important role in human development. The question arises as to whether Adenosine to Inosine RNA editing, catalyzed by the ADAR (Adenosine Deaminase acting on RNA) enzymes, differs in human embryogenesis and in adulthood. We tested the editing of various target genes in coding (FLNA, BLCAP, CYFIP2) and non-coding sequences at their Alu elements (BRCA1, CARD11, RBBP9, MDM4, FNACC), as well as the transcriptional levels of the ADAR1 enzymes.