A Resource for Discovering Specific and Universal Biomarkers for Distributed Stem Cells

Specific and universal biomarkers for distributed stem cells (DSCs) have been elusive. A major barrier to discovery of such ideal DSC biomarkers is difficulty in obtaining DSCs in sufficient quantity and purity. To solve this problem, we used cell lines genetically engineered for conditional asymmetric self-renewal, the defining DSC property. In gene microarray analyses, we identified 85 genes whose expression is tightly asymmetric self-renewal associated (ASRA). The ASRA gene signature prescribed DSCs to undergo asymmetric self-renewal to a greater extent than committed progenitor cells, embryonic stem cells, or induced pluripotent stem cells. This delineation has several significant implications. These include: 1) providing experimental evidence that DSCs in vivo undergo asymmetric self-renewal as individual cells; 2) providing an explanation why earlier attempts to define a common gene expression signature for DSCs were unsuccessful; and 3) predicting that some ASRA proteins may be ideal biomarkers for DSCs. Indeed, two ASRA proteins, CXCR6 and BTG2, and two other related self-renewal pattern associated (SRPA) proteins identified in this gene resource, LGR5 and H2A.Z, display unique asymmetric patterns of expression that have a high potential for universal and specific DSC identification

Intercolony variation in reproductive skipping in the African penguin

This is the final version. Available on open access from Wiley via the DOI in this recordData availability statement: The data underlying this article are available in the Dryad digital repository: https://doi.org/10.5061/dryad.0rxwdbs3z (Leith et al., 2022).In long-lived species, reproductive skipping is a common strategy whereby sexually mature animals skip a breeding season, potentially reducing population growth. This may be an adaptive decision to protect survival, or a non-adaptive decision driven by individual-specific constraints. Understanding the presence and drivers of reproductive skipping behavior can be important for effective population management, yet in many species such as the endangered African penguin (Spheniscus demersus), these factors remain unknown. This study uses multistate mark-recapture methods to estimate African penguin survival and breeding probabilities at two colonies between 2013 and 2020. Overall, survival (mean ± SE) was higher at Stony Point (0.82 ± 0.01) than at Robben Island (0.77 ± 0.02). Inter-colony differences were linked to food availability; under decreasing sardine (Sardinops sagax) abundance, survival decreased at Robben Island and increased at Stony Point. Additionally, reproductive skipping was evident across both colonies; at Robben Island the probability of a breeder becoming a nonbreeder was ~0.22, versus ~0.1 at Stony Point. Penguins skipping reproduction had a lower probability of future breeding than breeding individuals; this lack of adaptive benefit suggests reproductive skipping is driven by individual-specific constraints. Lower survival and breeding propensity at Robben Island places this colony in greater need of conservation action. However, further research on the drivers of inter-colony differences is needed.Association of Zoos and AquariumsBristol Zoological SocietyDepartment of Forestry, Fisheries, and the EnvironmentEarthwatch InstitutePew Charitable TrustsLeiden Conservation FoundationSANCCOBSan Diego Zoo Wildlife Allianc

SACK-Expanded Hair Follicle Stem Cells Display Asymmetric Nuclear Lgr5 Expression With Non-Random Sister Chromatid Segregation

We investigated the properties of clonally-expanded mouse hair follicle stem cells (HF-SCs) in culture. The expansion method, suppression of asymmetric cell kinetics (SACK), is non-toxic and reversible, allowing evaluation of the cells' asymmetric production of differentiating progeny cells. A tight association was discovered between non-random sister chromatid segregation, a unique property of distributed stem cells (DSCs), like HF-SCs, and a recently described biomarker, Lgr5. We found that nuclear Lgr5 expression was limited to the HF-SC sister of asymmetric self-renewal divisions that retained non-randomly co-segregated chromosomes, which contain the oldest cellular DNA strands, called immortal DNA strands. This pattern-specific Lgr5 association poses a potential highly specific new biomarker for delineation of DSCs. The expanded HF-SCs also maintained the ability to make differentiated hair follicle cells spontaneously, as well as under conditions that induced cell differentiation. In future human cell studies, this capability would improve skin grafts and hair replacement therapies

Toxicology evaluation of radiotracer doses of 3'-deoxy-3'-[18F]fluorothymidine (18F-FLT) for human PET imaging: Laboratory analysis of serial blood samples and comparison to previously investigated therapeutic FLT doses

Background: 18F-FLT is a novel PET radiotracer which has demonstrated a strong potential utility for imaging cellular proliferation in human tumors in vivo. To facilitate future regulatory approval of 18F-FLT for clinical use, we wished to demonstrate the safety of radiotracer doses of 18F-FLT administered to human subjects, by: 1) performing an evaluation of the toxicity of 18F-FLT administered in radiotracer amounts for PET imaging, 2) comparing a radiotracer dose of FLT to clinical trial doses of FLT. Methods: Twenty patients gave consent to a 18F-FLT injection, subsequent PET imaging, and blood draws. For each patient, blood samples were collected at multiple times before and after 18F-FLT PET. These samples were assayed for a comprehensive metabolic panel, total bilirubin, complete blood and platelet counts. 18F-FLT doses of 2.59 MBq/Kg with a maximal dose of 185 MBq (5 mCi) were used. Blood time-activity curves were generated for each patient from dynamic PET data, providing a measure of the area under the FLT concentration curve for 12 hours (AUC12). Results: No side effects were reported. Only albumin, red blood cell count, hematocrit and hemoglobin showed a statistically significant decrease over time. These changes are attributed to IV hydration during PET imaging and to subsequent blood loss at surgery. The AUC12 values estimated from imaging data are not significantly different from those found from serial measures of FLT blood concentrations (p = 0.66). The blood samples-derived AUC12 values range from 0.232 ng*h/mL to 1.339 ng*h/mL with a mean of 0.802 � 0.303 ng*h/mL. This corresponds to 0.46% to 2.68% of the lowest and least toxic clinical trial AUC12 of 50 ng*h/mL reported by Flexner et al (1994). This single injection also corresponds to a nearly 3,000-fold lower cumulative dose than in Flexner's twice daily trial. Conclusion: This study shows no evidence of toxicity or complications attributable to 18F-FLT injected intravenously.This study was supported by NIH grant R01 CA115559, 1R01 CA107264, and 1R01 CA80907

CXCR6, a Newly Defined Biomarker of Tissue-Specific Stem Cell Asymmetric Self-Renewal, Identifies More Aggressive Human Melanoma Cancer Stem Cells

Background: A fundamental problem in cancer research is identifying the cell type that is capable of sustaining neoplastic growth and its origin from normal tissue cells. Recent investigations of a variety of tumor types have shown that phenotypically identifiable and isolable subfractions of cells possess the tumor-forming ability. In the present paper, using two lineage-related human melanoma cell lines, primary melanoma line IGR39 and its metastatic derivative line IGR37, two main observations are reported. The first one is the first phenotypic evidence to support the origin of melanoma cancer stem cells (CSCs) from mutated tissue-specific stem cells; and the second one is the identification of a more aggressive subpopulation of CSCs in melanoma that are CXCR6+. Conclusions/Significance: The association of a more aggressive tumor phenotype with asymmetric self-renewal phenotype reveals a previously unrecognized aspect of tumor cell physiology. Namely, the retention of some tissue-specific stem cell attributes, like the ability to asymmetrically self-renew, impacts the natural history of human tumor development. Knowledge of this new aspect of tumor development and progression may provide new targets for cancer prevention and treatment

Incorporating one health into medical education

One Health is an emerging concept that stresses the linkages between human, animal, and environmental health, as well as the need for interdisciplinary communication and collaboration to address health issues including emerging zoonotic diseases, climate change impacts, and the human-animal bond. It promotes complex problem solving using a systems framework that considers interactions between humans, animals, and their shared environment. While many medical educators may not yet be familiar with the concept, the One Health approach has been endorsed by a number of major medical and public health organizations and is beginning to be implemented in a number of medical schools. In the research setting, One Health opens up new avenues to understand, detect, and prevent emerging infectious diseases, and also to conduct translational studies across species. In the clinical setting, One Health provides practical ways to incorporate environmental and animal contact considerations into patient care. This paper reviews clinical and research aspects of the One Health approach through an illustrative case updating the biopsychosocial model and proposes a basic set of One Health competencies for training and education of human health care providers

Mammary stem cells, self-renewal pathways, and carcinogenesis

The mammary gland epithelial components are thought to arise from stem cells that undergo both self-renewal and differentiation. Self-renewal has been shown to be regulated by the Hedgehog, Notch, and Wnt pathways and the transcription factor B lymphoma Mo-MLV insertion region 1 (Bmi-1). We review data about the existence of stem cells in the mammary gland and the pathways regulating the self-renewal of these cells. We present evidence that deregulation of the self-renewal in stem cells/progenitors might be a key event in mammary carcinogenesis. If 'tumor stem cells' are inherently resistant to current therapies, targeting stem cell self-renewal pathways might provide a novel approach for breast cancer treatment