Stem Cells and Progenitors in Human Peripheral Blood Get Activated by Extremely Active Resveratrol (XAR™)
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.
KeywordsStem cells VSELs Resveratrol OCT-4 Regeneration Aging Tumor suppression
Compliance with Ethical Standards
Conflict of Interest
VT, SC, VJ and AT are affiliated to Epigeneres Biotech Pvt. Ltd. which manufactures and has patented XAR™.
- 2.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.CrossRefPubMedPubMedCentralGoogle Scholar
- 6.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.CrossRefPubMedPubMedCentralGoogle Scholar
- 7.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.CrossRefPubMedPubMedCentralGoogle Scholar
- 8.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.CrossRefGoogle Scholar
- 9.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.CrossRefPubMedPubMedCentralGoogle Scholar
- 12.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.CrossRefPubMedGoogle Scholar
- 13.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.CrossRefPubMedGoogle Scholar
- 14.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.CrossRefPubMedGoogle Scholar
- 15.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.
- 17.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.
- 18.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.CrossRefPubMedGoogle Scholar
- 24.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.CrossRefPubMedGoogle Scholar
- 27.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.CrossRefPubMedGoogle Scholar
- 28.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.CrossRefPubMedPubMedCentralGoogle Scholar
- 30.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.
- 31.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.CrossRefPubMedPubMedCentralGoogle Scholar
- 32.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.CrossRefPubMedPubMedCentralGoogle Scholar