A significant risk in the clinical application of human pluripotent stem cells (hPSCs), including human embryonic and induced pluripotent stem cells (hESCs and hiPSCs), is teratoma formation from residual undifferentiated cells. We have raised a monoclonal antibody (mAb) against hESCs, designated SSEA-5, which binds a novel antigen highly and specifically expressed on hPSCs--the H type-1 glycan. Separation of SSEA-5 high cells through fluorescence-activated cell sorting (FACS) drastically reduced teratoma formation potential. To ensure complete removal we identified additional markers exhibiting a large dynamic expression range during differentiation: CD9, CD30, CD50, CD90, and CD200. Immunohistochemistry (IHC) conducted on human fetal tissues and bioinformatics analysis of a microarray database revealed that concurrent expression of these markers is both common and specific to hPSCs. When applied to incompletely differentiated hESC cultures, immunodepletion with SSEA-5 and 2 additional markers completely removed teratoma formation potential.
Background Smartwatch and fitness band wearable consumer electronics can passively measure pulse rate from the wrist using photoplethysmography (PPG). Identification of pulse irregularity or variability from these data has the potential to identify atrial fibrillation or atrial flutter (AF, collectively). The rapidly expanding consumer base of these devices allows for detection of undiagnosed AF at scale. Methods The Apple Heart Study is a prospective, single arm pragmatic study that has enrolled 419,093 participants ( NCT03335800 ). The primary objective is to measure the proportion of participants with an irregular pulse detected by the Apple Watch (Apple Inc, Cupertino, CA) with AF on subsequent ambulatory ECG patch monitoring. The secondary objectives are to: 1) characterize the concordance of pulse irregularity notification episodes from the Apple Watch with simultaneously recorded ambulatory ECGs; 2) estimate the rate of initial contact with a health care provider within 3 months after notification of pulse irregularity. The study is conducted virtually, with screening, consent and data collection performed electronically from within an accompanying smartphone app. Study visits are performed by telehealth study physicians via video chat through the app, and ambulatory ECG patches are mailed to the participants. Conclusions The results of this trial will provide initial evidence for the ability of a smartwatch algorithm to identify pulse irregularity and variability which may reflect previously unknown AF. The Apple Heart Study will help provide a foundation for how wearable technology can inform the clinical approach to AF identification and screening. (Am Heart J 2019;207:66–75.)
Objective Enhancement of human cardiac progenitor cell (hCPC) reparative and regenerative potential by genetic modification for treatment of myocardial infarction. Background Regenerative potential of stem cells to repair acute infarction is limited. Improved hCPC survival, proliferation and differentiation into functional myocardium will increase efficacy and advance translational implementation of cardiac regeneration. Methods hCPCs isolated from myocardium of heart failure patients undergoing left ventricular assist device (LVAD) implantation are engineered to express green fluorescent protein (GFP; hCPCe) or Pim-1-GFP (hCPCeP). Functional tests of hCPC regenerative potential are performed with immunocompromised mice by intramyocardial adoptive transfer injection after infarction. Myocardial structure and function is monitored by echocardiographic and hemodynamic assessment for 20 weeks following delivery. hCPCe and hCPCeP expressing luciferase are followed by bioluminesence imaging (BLI) to non-invasively track persistence. Results hCPCeP exhibit augmentation of reparative potential relative to hCPCe control cells as demonstrated by significantly increased proliferation coupled with amelioration of infarction injury and increased hemodynamic performance at 20 weeks post-transplantation. Concurrent with enhanced cardiac structure and function, hCPCeP demonstrate increased cellular engraftment and differentiation with improved vasculature and reduced infarct size. Enhanced persistence of hCPCeP versus hCPCe is revealed by BLI at up to 8 weeks post delivery. Conclusion Genetic engineering of hCPCs with Pim-1 enhances repair of damaged myocardium. Ex vivo gene delivery to modify stem cells has emerged as a viable option addressing current limitations in the field. This study demonstrates that efficacy of human CPCs from the failing myocardium can be safely and significantly enhanced through expression of Pim-1 kinase, setting the stage for use of engineered cells in preclinical settings.
Organs are composites of tissue types with diverse developmental origins, and they rely on distinct stem and progenitor cells to meet physiological demands for cellular production and homeostasis. How diverse stem cell activity is coordinated within organs is not well understood. Here we describe a lineage-restricted, self-renewing common skeletal progenitor (bone, cartilage, stromal progenitor; BCSP) isolated from limb bones and bone marrow tissue of fetal, neonatal, and adult mice. The BCSP clonally produces chondrocytes (cartilage-forming) and osteogenic (bone-forming) cells and at least three subsets of stromal cells that exhibit differential expression of cell surface markers, including CD105 (or endoglin), Thy1 [or CD90 (cluster of differentiation 90)], and 6C3 [ENPEP glutamyl aminopeptidase (aminopeptidase A)]. These three stromal subsets exhibit differential capacities to support hematopoietic (blood-forming) stem and progenitor cells. Although the 6C3-expressing subset demonstrates functional stem cell niche activity by maintaining primitive hematopoietic stem cell (HSC) renewal in vitro, the other stromal populations promote HSC differentiation to more committed lines of hematopoiesis, such as the B-cell lineage. Gene expression analysis and microscopic studies further reveal a microenvironment in which CD105-, Thy1-, and 6C3-expressing marrow stroma collaborate to provide cytokine signaling to HSCs and more committed hematopoietic progenitors. As a result, within the context of bone as a blood-forming organ, the BCSP plays a critical role in supporting hematopoiesis through its generation of diverse osteogenic and hematopoietic-promoting stroma, including HSC supportive 6C3(+) niche cells.endochondral ossification | lymphopoiesis
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