Abstract
Resveratrol generated enormous interest as it improved functions of multiple organs and could delay aging in animal models. However, basic mechanism of action was not understood and due to poor bioavailability, it has failed to enter the market. A highly active nano-formulation of resveratrol (XAR™) with enhanced bioavailability is now available. Present study was undertaken to evaluate its effects on stem cells biology in the human peripheral blood. Twelve healthy participants were enrolled of which five received XAR™, five were age-matched placebo controls and two were 76 and 85 years old. Peripheral blood was processed to study serum profile to monitor cardiac and pancreatic functions and subjected to density gradient centrifugation to enrich pluripotent (VSELs) and adult stem cells that get enriched along with red blood cells and in the Buffy coat respectively on Day 2 and Day 15 after XAR™ treatment. The XAR™ treatment resulted in an increased expression of pluripotency transcripts specific for VSELs (Oct-4A, Nanog and Sox2) on D2; specific transcripts for differentiation in the progenitors including Oct-4, Ikaros, CD14, CD90 on D15, and anti-ageing and tumor suppressor transcripts NAD, SIRT1, SIRT6 and p53 in both stem cells and progenitors. An improvement of cardiac and pancreatic markers in serum profile was also observed on D15. The decline in VSELs numbers with age and beneficial effects of the XAR™ treatment were evident by up-regulation of specific transcripts and on serum profile. XAR™ is a promising molecule that has the potential to activate pluripotent VSELs and tissue committed adult stem cells ‘progenitors’ resulting in the rejuvenation of various body tissues and for improved, cancer-free health with advanced age.
Similar content being viewed by others
References
Howitz, K., Bitterman, J., & Cohen, H. (2003). Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature, 425(September), 191–196. https://doi.org/10.1038/nature01965.1.
Pacholec, M., Bleasdale, J. E., Chrunyk, B., Cunningham, D., Flynn, D., Garofalo, R. S., … Ahn, K. (2010). SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1. Journal of Biological Chemistry, 285(11), 8340–8351. https://doi.org/10.1074/jbc.M109.088682.
Hubbard, B. P., Gomes, A. P., Dai, H., Li, J., Case, A. W., Riera, T. V., … David, A. (2013). Evidence for a common mechanism of SIRT1 regulation by allosteric activators. Science, 339(6124), 1216–1219. https://doi.org/10.1126/science.1231097.
Hubbard, B. P., & Sinclair, D. A. (2013). Measurement of sirtuin enzyme activity using a substrate- agnostic fluorometric nicotinamide assay. Methods in Molecular Biology, 1077, 167–177. https://doi.org/10.1007/978-1-62703-637-5.
Bonkowski, M. S., & Sinclair, D. A. (2016). Slowing ageing by design: the rise of NAD + and sirtuin-activating compounds. Nature Reviews Molecular Cell Biology, 17(11), 679–690. https://doi.org/10.1038/nrm.2016.93.
Subramanian, L., Youssef, S., Bhattacharya, S., Kenealey, J., Polans, A. S., & van Ginkel, P. R. (2010). Resveratrol: challenges in translation to the clinic — a critical discussion. Clinical Cancer Research, 16(24), 5942–5948. https://doi.org/10.1016/j.immuni.2010.12.017.
Ratajczak, M. Z., Ratajczak, J., Suszynska, M., Miller, D. M., Kucia, M., & Shin, D. M. (2017). A novel view of the adult stem cell compartment from the perspective of a quiescent population of very small embryonic-like stem cells. Circulation Research, 120(1), 166–178. https://doi.org/10.1161/CIRCRESAHA.116.309362.
Bhartiya, D., Shaikh, A., Anand, S., Patel, H., Kapoor, S., Sriraman, K., … Unni, S. (2016). Endogenous, very small embryonic-like stem cells: critical review, therapeutic potential and a look ahead. Human Reproduction Update, 23(1), 1–36. https://doi.org/10.1093/humupd/dmw030.
Ratajczak, M. Z., Shin, D. M., Liu, R., Mierzejewska, K., Ratajczak, J., Kucia, M., & Zuba-Surma, E. K. (2012). Very small embryonic/epiblast-like stem cells (VSELs) and their potential role in aging and organ rejuvenation - An update and comparison to other primitive small stem cells isolated from adult tissues. Aging, 4(4), 235–246.
Ratajczak, M. Z., Bartke, A., & Darzynkiewicz, Z. (2017). Prolonged growth hormone/insulin/insulin-like growth factor nutrient response signaling pathway as a silent killer of stem cells and a culprit in aging. Stem Cell Reviews and Reports. https://doi.org/10.1007/s12015-017-9728-2.
Galkowski, D., Ratajczak, M. Z., Kocki, J., & Darzynkiewicz, Z. (2017). Of cytometry, stem cells and fountain of youth. Stem Cell Reviews and Reports. https://doi.org/10.1007/s12015-017-9733-5.
Shaikh, A., Anand, S., Kapoor, S., Ganguly, R., & Bhartiya, D. (2017). Mouse bone marrow VSELs exhibit differentiation into three embryonic germ lineages and germ & hematopoietic cells in culture. Stem Cell Reviews and Reports, 13(12), 202–216. https://doi.org/10.1007/s12015-016-9714-0.
Havens, A. M., Sun, H., Shiozawa, Y., Jung, Y., Wang, J., Mishra, A., … Taichman, R. S. (2014). Human and murine very small embryonic-like cells represent multipotent tissue progenitors, in vitro and in vivo. Stem Cells and Development, 23(7), 689–701. https://doi.org/10.1089/scd.2013.0362.
Kucia, M., Reca, R., Campbell, F. R., Zuba-Surma, E., Majka, M., Ratajczak, J., & Ratajczak, M. Z. (2006). A population of very small embryonic-like (VSEL) CXCR4(+)SSEA-1(+)Oct-4 + stem cells identified in adult bone marrow. Leukemia, 20(5), 857–869. https://doi.org/10.1038/sj.leu.2404171.
Monti, M., Imberti, B., Bianchi, N., Pezzotta, A., Morigi, M., Fante, D., C., … Perotti, C (2017). A novel method for the isolation of pluripotent stem cells from human umbilical cord blood. Stem Cells and Development. https://doi.org/10.1089/scd.2017.0012.
Abbott, A. (2013). Doubt cast over tiny stem cells. Nature, 499(7459), 390. https://doi.org/10.1038/499390a.
Bhartiya, D. (2017). Pluripotent stem cells in adult tissues: struggling to be acknowledged over two decades. Stem Cell Reviews and Reports, 1–12. https://doi.org/10.1007/s12015-017-9756-y.
Bhartiya, D., Shaikh, A., Nagvenkar, P., Kasiviswanathan, S., Pethe, P., Pawani, H., … Hinduja, I. (2012). Very small embryonic-like stem cells with maximum regenerative potential get discarded during cord blood banking and bone marrow processing for autologous stem cell therapy. Stem Cells and Development, 21(1), 1–6. https://doi.org/10.1089/scd.2011.0311.
Shaikh, A., Nagvenkar, P., Pethe, P., Hinduja, I., & Bhartiya, D. (2015). Molecular and phenotypic characterization of CD133 and SSEA4 enriched very small embryonic-like stem cells in human cord blood. Leukemia, 29(9), 1909–1917. https://doi.org/10.1038/leu.2015.100.
Bhartiya, D. (2017). Do adult somatic cells undergo reprogramming or endogenous pluripotent stem cells get activated to account for plasticity, regeneration and cancer initiation? Stem Cell Reviews and Reports. https://doi.org/10.1007/s12015-017-9749-x.
Boyer, L. A., Lee, T. I., Cole, M. F., Johnstone, S. E., Levine, S. S., Zucker, J. P., … Young, R. A. (2005). Core transcriptional regulatory circuitry in human embryonic stem cells. Cell, 122(6), 947–956. https://doi.org/10.1016/j.cell.2005.08.020.
Bhartiya, D. (2015). Ovarian stem cells are always accompanied by very small embryonic-like stem cells in adult mammalian ovary. Journal of Ovarian Research, 8(1), 70. https://doi.org/10.1186/s13048-015-0200-0.
Shaikh, A., Bhartiya, D., Kapoor, S., & Nimkar, H. (2016). Delineating the effects of 5-fluorouracil and follicle-stimulating hormone on mouse bone marrow stem/progenitor cells. Stem Cell Research & Therapy, 7(1), 59. https://doi.org/10.1186/s13287-016-0311-6.
Kucia, M., Halasa, M., Wysoczynski, M., Baskiewicz-Masiuk, M., Moldenhawer, S., Zuba-Surma, E., … Ratajczak, M. Z. (2007). Morphological and molecular characterization of novel population of CXCR4 + SSEA-4 + Oct-4 + very small embryonic-like cells purified from human cord blood – preliminary report. Leukemia, 21(2), 297–303. https://doi.org/10.1038/sj.leu.2404470.
Liedtke, S., Stephan, M., & Kögler, G. (2008). Oct4 expression revisited: potential pitfalls for data misinterpretation in stem cell research. Biological Chemistry, 389(7), 845–850. https://doi.org/10.1515/BC.2008.098.
Wang, X., & Dai, J. (2010). Concise review: isoforms of Oct4 contribute to the confusing diversity in stem cell biology. Stem Cells, 28(5), 885–893. https://doi.org/10.1002/stem.419.
Tseng, P. C., Hou, S. M., Chen, R. J., Peng, H. W., Hsieh, C. F., Kuo, M. L., & Yen, M. L. (2011). Resveratrol promotes osteogenesis of human mesenchymal stem cells by upregulating RUNX2 gene expression via the SIRT1/FOXO3A axis. Journal of Bone and Mineral Research, 26(10), 2552–2563. https://doi.org/10.1002/jbmr.460.
Peltz, L., Gomez, J., Marquez, M., Alencastro, F., Atashpanjeh, N., Quang, T., … Zhao, Y. (2012). Resveratrol exerts dosage and duration dependent effect on human mesenchymal stem cell development. PLoS ONE, 7(5), e37162. https://doi.org/10.1371/journal.pone.0037162.
Ling, L., Gu, S., & Cheng, Y. (2017). Resveratrol activates endogenous cardiac stem cells and improves myocardial regeneration following acute myocardial infarction. Molecular Medicine Reports, 15(3), 1188–1194. https://doi.org/10.3892/mmr.2017.6143.
Zuba-surma, E. K., Kucia, M., Dawn, B., Guo, Y., Ratajczak, Z., M., & Bolli, R. (2008). Bone marrow-derived pluripotent very small embryonic-like stem cells (VSELs) are mobilized after acute myocardial infarction. Journal of Molecular and Cellular Cardiology, 44(5), 865–873. https://doi.org/10.1016/j.yjmcc.2008.02.279.Bone.
Wojakowski, W., Tendera, M., Kucia, M., Zuba-Surma, E., Paczkowska, E., Ciosek, J., … Ratajczak, M. Z. (2009). Mobilization of bone marrow-derived Oct-4 + SSEA-4 + very small embryonic-like stem cells in patients with acute myocardial infarction. Journal of the American College of Cardiology, 53(1), 1–9. https://doi.org/10.1016/j.jacc.2008.09.029.
Sebastián, C., Zwaans, B. M. M., Silberman, D. M., Gymrek, M., Goren, A., Zhong, L., … Mostoslavsky, R. (2012). The histone deacetylase SIRT6 Is a tumor suppressor that controls cancer metabolism. Cell, 151(6), 1185–1199. https://doi.org/10.1016/j.cell.2012.10.047.
Dasgupta, B., & Milbrandt, J. (2007). Resveratrol stimulates AMP kinase activity in neurons. Proceedings of the National Academy of Sciences, 104(17), 7217–7222. https://doi.org/10.1073/pnas.0610068104.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
VT, SC, VJ and AT are affiliated to Epigeneres Biotech Pvt. Ltd. which manufactures and has patented XAR™.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Tripathi, V., Chhabria, S., Jadhav, V. et al. Stem Cells and Progenitors in Human Peripheral Blood Get Activated by Extremely Active Resveratrol (XAR™). Stem Cell Rev and Rep 14, 213–222 (2018). https://doi.org/10.1007/s12015-017-9784-7
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12015-017-9784-7