Very Small Embryonic-like Stem Cells A. Introduction 1. Found in Bone Marrow The authors identified a rare population of small open-type chromatin typical of embryonic stem cells. These cells are able to differentiate into all three germ-layer lineages. The number of these cells is highest in bone marrow from young 1-month old mice and decreases with age. The small embryonic-like cell is significantly diminished in short living mice as compared to long living animals. These very small embryonic-liked (VSEL) stem cells appear to be deposited early during development in the bone marrow and could be a source of pluripotent stem cells for tissue and organ regeneration. Kucia M, Reca R, Campbell FR, Zuba-Surma E, Maika M, Rataiczak J, Rataiczak MZ. A population of very small embryonic-like (VSEL) CXCR4(+)SSEA-1(+) Oct-4+ stem cells identified in adult bone marrow. Leukemia 2006;20(5):857-69. on-line reference 2. Found in Umbilical Cord Blood The authors found the very small embryonic-like stem cells in umbilical cord blood. Kucia M, Halasa M, Wysoczynski M, Baskiewicz-Masiuk M, Moldenhawer S, Zuba-Suma E, Czajka R, Wojakowski W, Machalinski B, Ratajczak MZ. Morphological and molecular characterization of novel population of CXCR4+ SSEA-4+ very small embryonic-like cells purified from human cord blood: preliminary report. Leukemia 2007;21(2):297-303. on-line reference 3. VSEL stem cells also have germ cell characteristics The authors identified a population of very small embryonic-like (VSEL) stem cells in the bone marrow that express epiblast/germ line-derived primordial germ cell markers. Pluripotent epiblast/primordial germ cells may persist beyond embryogenesis in neonatal and adult tissues. The authors conclude that these cells play an important role in tissue and organ regeneration and their presence in adult tissues may explain the phenomenon of stem cell plasticity. In pathological situations, however, they may undergo malignant transformation and give rise to tumors. Kucia M, Machalinski B, Ratajczak MZ. The developmental deposition of epiblast/germ cell-line derived cells in various organs as a hypothetical explanation of stem cell plasticity? Acta Neurobiol Exp (Wars):2006;66(4):331-41. on-line reference 4. Can VSEL stem cells and Cancer Stem Cells Growing tumors appear to contain some vary primitive cells that are mobile and endowed with metastatic potential. The authors suggest that the process of pathological metastasis of cancer cells reflects a property of normal stem cells and their ability to migrate. Highly migratory VSEL stem cells could give rise to some primitive types of tumors and be involved in tumor angiogenesis and the formation of tumor stroma. Ratajczak M, Tarnowski M, Staniszewska M, Sroczynski T, Banach B. Mechanisms of cancer metastasis: involvement of cancer stem cells? Minerva Med 2010;101(3):179-91. on-line reference 5. Heart Disease The VSEL stem cells have shown that they can differentiate into cardiomyocytes (heart cells) in culture. The stem cells were administered to mice models of myocardial infarction. The VSEL stem cells improved their left ventricular systolic function, compared to the control mice, and alleviated myocyte hypertrophy after the heart attack. Dawn B, Tiwari S, Kucia MJ, Zuba-Surma EK, Guo Y, Sanganalmath SK, Abdel-Latif A, Hunt G, Vincent RJ, Taher H, Reed NJ, Ratajczak MZ, Bolli R. Transplantation of bone marrow-derived very small embryonic-like stem cells attenuates left ventricular dysfunction and remodeling after myocardial infarction. Stem Cells 2008;26(6):1646-55. on-line reference b. Mobilization in mice after a heart attack VESEL stem cells were mobilized in mice from the bone marrow into the peripheral blood after an acute myocardial infarction. Zuba-Suma EK, Kucia M, Dawn B, Guo Y, Ratajczak MZ, Bolli R. Bone marrow-derived pluripotent very small embryonic-like stem cells (VSELs) are moblized after acute myocardial infarction. J Mol Cell Cardiol 2008; 44(5):865-73. on-line reference c. Mobilization in humans after a heart attack VSELs were mobilized early in patients having an acute heart attack and remained elevated after 24 hours and after 5 days. The mobilization of VESEL was significantly reduced in patients over 50 years of age and in those with diabetes. Wojakowski W, Tendera M, Kucia M, Zuba-Surma E, Paczkowska E, Ciosek J, Halasa M, Król M, Kazmierski M, Buszman P, Ochala A, Ratajczak J, Machalinski B, Ratajczak MZ. Mobilization of bone marrow-derived Oct-4+ SSEA-4+ very small embryonic-like stem cells in patients with acute myocardial infarction. J Am Coll Cardiol 2009;53(1):1-9. on-line reference d. Mobilization in humans after a stroke The authors found an increase in the number of circulating CD34 (hematopoietic stem cells), CD133 (primitive neural progenitors), and VSEL stem cells. Paczkowska E1, Kucia M, Koziarska D, Halasa M, Safranow K, Masiuk M, Karbicka A, Nowik M, Nowacki P, Ratajczak MZ, Machalinski B. Clinical evidence that very small embryonic-like stem cells are mobilized into peripheral blood in patients after stroke. Stroke 2009;40(4):1237-44. on-line reference 6. Developmental links The authors showed through genetics, evidence of a potential developmental link between germline cells, VESELs and hematopoietic stem cells. Suszynska M, Poniewierska-Baran A, Gunjal P, Ratajczak J, Marycz K, Kakar SS, Kucia M, Ratajczak MZ Expression of the erythropoietin receptor by germline-derived cells - further support for a potential developmental link between the germline and hematopoiesis. J Ovarian Res 2014;7:66. on-line reference B. Treatments 1. Diabetes Very small embryonic-like stem cells were intravenously administered to mouse and migrated into the pancreas and survived in a diabetic pancreas. In the treated groups, blood glucose significantly decreased for at least two months. Abouzaripour M, Ragerdi Kashani I, Pasbakhsh P, Atlasy N. Intravenous transplantation of very small embryonic like stem cells in treatment of diabetes mellitus. Avicenna J Med Biotechnol 2015, 7(1):22-31. on-line reference 2. Leg Ischemia A mouse model of leg ischemia (lack of blood flow) were administered very small embryonic-like stem cells (VSEL) stem cells. VSEL-derived cells showed a pattern of secretion similar to the endothelial progenitor cells, releasing low levels of vascular endothelial growth factor-A (VEGF) and inflammatory cytokines. Post-ischemic angiogenesis (production of new blood vessels) in the mice. VSEL stem cells are a potential new source of cells for endothelial function in humans. Guerin CL, Loyer X, Vilar J, Cras A, Mirault T, Gaussem P, Silvestre JS, Smadja DM. Bone-marrow-derived very small embryonic-like stem cells in patients with critical leg ischaemia: evidence of vasculogenic potential. Thromb Haemost 2015;113(5):1084-94. on-line reference 3. Liver Repair Stem Cell Factor (SCF), in the presence of hepatic growth factor promoted VESEL differentiation into liver tissue. The VESEL stem cells were transplanted into injured livers and proceeded to repair the damage. Chen ZH1, Lv X, Dai H, Liu C, Lou D, Chen R, Zou GM. Hepatic regenerative potential of mouse bone marrow very small embryonic-like stem cells. J Cell Physiol 2015;230(8):1852-61. on-line reference