Thymidine analogs, including bromodeoxyuridine, chlorodeoxyuridine, iododeoxyuridine, and tritiated thymidine, label dividing cells by incorporating into DNA during S phase of cell division and are widely employed to identify cells transplanted into the central nervous system. However, the potential for transfer of thymidine analogs from grafted cells to dividing host cells has not been thoroughly tested. We here demonstrate that graft-derived thymidine analogs can become incorporated into host neural precursors and glia. Large numbers of labeled neurons and glia were found 3-12 weeks after transplantation of thymidine analog-labeled live stem cells, suggesting differentiation of grafted cells. Remarkably, however, similar results were obtained after transplantation of dead cells or labeled fibroblasts. Our findings reveal for the first time that thymidine analog labeling may not be a reliable means of identifying transplanted cells, particularly in highly proliferative environments such as the developing, neurogenic, or injured brain.

Stroke represents an attractive target for stem cell therapy. Although different types of cells have been employed in animal models, a direct comparison between cell sources has not been performed. The aim of our study was to assess the effect of human multipotent adult progenitor cells (hMAPCs) and human mesenchymal stem cells (hMSCs) on endogenous neurogenesis, angiogenesis and inflammation following stroke. BALB/Ca-RAG 2−/− γC−/− mice subjected to FeCl3 thrombosis mediated stroke were intracranially injected with 2×105 hMAPCs or hMSCs 2 days after stroke and followed for up to 28 days. We could not detect long-term engraftment of either cell population. However, in comparison with PBS-treated animals, hMSC and hMAPC grafted animals demonstrated significantly decreased loss of brain tissue. This was associated with increased angiogenesis, diminished inflammation and a glial-scar inhibitory effect. Moreover, enhanced proliferation of cells in the subventricular zone (SVZ) and survival of newly generated neuroblasts was observed. Interestingly, these neuroprotective effects were more pronounced in the group of animals treated with hMAPCs in comparison with hMSCs. Our results establish cell therapy with hMAPCs and hMSCs as a promising strategy for the treatment of stroke.

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As an important component of tumor microenvironment, cancer-associated fibroblasts (CAFs) have lately gained prominence owing to their crucial role in the resistance to therapies. Photodynamic therapy (PDT) stands out as a successful therapeutic strategy to treat cutaneous squamous cell carcinoma. In this study, we demonstrate that the transforming growth factor β1 (TGFβ1) cytokine secreted by CAFs isolated from patients with SCC can drive resistance to PDT in epithelial SCC cells. To this end, CAFs obtained from patients with in situ cSCC were firstly characterized based on the expression levels of paramount markers as well as the levels of TGFβ1 secreted to the extracellular environment. On a step forward, two established human cSCC cell lines (A431 and SCC13) were pre-treated with conditioned medium obtained from the selected CAF cultures. The CAF-derived conditioned medium effectively induced resistance to PDT in A431 cells through a reduction in the cell proliferation rate. This resistance effect was recapitulated by treating with recombinant TGFβ1 and abolished by using the SB525334 TGFβ1 receptor inhibitor, providing robust evidence of the role of TGFβ1 secreted by CAFs in the development of resistance to PDT in this cell line. Conversely, higher levels of recombinant TGFβ1 were needed to reduce cell proliferation in SCC13 cells, and no induction of resistance to PDT was observed in this cell line in response to CAF-derived conditioned medium. Interestingly, we probed that the comparatively higher intrinsic resistance to PDT of SCC13 cells was mediated by the elevated levels of TGFβ1 secreted by this cell line. Our results point at this feature as a promising biomarker to predict both the suitability of PDT and the chances to optimize the treatment by targeting CAF-derived TGFβ1 in the road to a more personalized treatment of particular cSCC tumors.

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The Notch signaling pathway is a multifunctional, evolutionarily conserved pathway, which plays an important role in development as well as stem cell biology. Multipotent adult progenitor cells (MAPCs) represent a unique stem cell population, which is capable of differentiating into cell types of the ectodermal, mesodermal and endodermal lineages in vitro, and contribute to most somatic cell types in vivo. Our aim was to characterize the gene expression of Notch signaling elements in rodent MAPCs. We show that transcripts for Notch-receptors, ligands, regulatory molecules of the pathway and the Hairy/Enhancer of Split-1 (HES-1) target gene are present in mouse and rat low-Oct4 MAPCs. We found that mouse Notch3 and rat Notch1 transcripts increased when cells were cultured at high density for 48 to 96 hours. HES-1 and HES-related transcription factor-1 (HERP-1), transcriptional targets of Notch-signaling, were both elicited by immobilized Delta1 ligand. In addition, mRNA for Notch1 and Notch3 was also induced by Notch-signaling, suggesting the presence of regulatory feedback loops. Slight differences between mouse and rat derived MAPCs suggest that the exact function, transcriptional regulation and the fine-tuning of the signal may be species specific. Taken together, we characterized the gene expression profile of the Notch pathway in rodent low-Oct4-MAPCs, and showed that the pathway is functional and can be modulated. Our results provide an additional tool and a further basis for a better understanding of stem cell biology.

The impact of the interaction of all combined environmental agents to which an individual is exposed during his/her lifetime, as well as how his/her organism responds to these influences, defines health, aging, and disease. The systematic, integrative characterization of the different elements making up the “exposome” is thus necessary to identify and exploit the potential of compounds capable of conferring protection with minimal side effects. Extracts from the natural world, containing synergistic combinations of compounds with antioxidant and protective properties, have long been used in traditional medicine. Modern science has the opportunity to leverage these substances honed by evolution and use them safely and reliably, with a profound mechanistic knowledge and guaranteeing standardization and absence of toxicity. Here, we discuss our current knowledge regarding the potential of a soluble extract of the hair grass Deschampsia antarctica (as its standardized commercial preparation Edafence®) to counteract the skin exposome and its impact on skin aging and disease.

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