STEM CELLS

Co-investigator: Prof. G alderisi Umberto, Prof. Di Bernardo Giovanni, Dr. Alessio Nicola, Dr. Squillaro Tiziana, Dr. Aprile Domenico, Dr. Sura H. A. Al-sammarraie

In adulthood, tissue-specific stem cells regulate homeostatic tissue regeneration. Stem cells are located in specific areas of tissues, called niches, and are characterized as being in a state of relative proliferative quiescence, from which they can exit under the proper conditions to obtain the proliferative potential necessary for tissue regeneration.

Stem cells reside for long periods of time in our bodies, and this increases the possibility that they may be subjected to genotoxic damage, which may derive from extrinsic (ionizing radiation, drugs, chemicals, etc.) or intrinsic sources (DNA replication errors, spontaneous chemical changes to DNA, programmed DNA recombination). Following damage, cells may properly repair DNA and restore functionality, or they may accumulate irreversible damages that trigger either apoptosis or senescence. Alternatively, damaged cells may undergo transformation with the onset of cancer.

Mesenchymal stromal cells (MSCs) are present in the stroma of several organs and tissues, such as bone marrow, adipose tissue, dental pulp, and umbilical cord.

MSCs are not a homogenous population but comprehend several cell types, such as stem cells, progenitor cells, fibroblasts, and other types of cells. Stem cells present in an MSC population can differentiate into mesodermal lineage cells (adipocytes, chondrocytes, osteocytes, and muscle cells) but also in cells belonging to endodermal and ectodermal lineages, at least in vitro. For this reason, several researchers proposed that MSCs may contain a subpopulation of pluripotent stem cells. Indeed, in the past, several authors have identified putative pluripotent stem cells in MSCs, such as multipotent adult progenitor cells (MAPCs) or very small embryonic stem cells (VSELs). Many scientists questioned the existence of these cells. In recent years, the Dezawa's research group identified a population of pluripotent stem cells, which represent around 1-3% of MSCs. These cells were named multilineagedifferentiating stress enduring (Muse) cells since they were found to be stress-tolerant cells. Muse cells express the pluripotent surface marker SSEA-3 and other pluripotency genes (NANOG, OCT-3/4, SOX2). They can differentiate into triploblastic cells from a single cell and are self-renewable.

In MSC cultures, other cell types do not possess the properties of Muse cells. Indeed, Muse cells, isolated from a heterogeneous stromal cell culture, can differentiate into functional melanocytes, while non-Muse cells fail to do so. In an animal model of stroke, Muse cells can replenish lost neurons and contribute to pyramidal tract reconstruction. Muse cells can also differentiate into liver cells when intravenously injected into animals that were subjected to hepatectomy. All these studies indicate that Muse cells are pluripotent, but non-Muse cells in MSC cultures are not.

OUR Publications:

1: Squillaro T, Alessio N, Di Bernardo G, Özcan S, Peluso G, Galderisi U. Stem Cells and DNA Repair Capacity: Muse Stem Cells Are Among the Best Performers. Adv Exp Med Biol. 2018;1103:103-113. doi: 10.1007/978-4-431-56847-6_5. PubMed PMID: 30484225.

2: Alessio N, Pipino C, Mandatori D, Di Tomo P, Ferone A, Marchiso M, Melone MAB, Peluso G, Pandolfi A, Galderisi U. Mesenchymal stromal cells from amniotic fluid are less prone to senescence compared to those obtained from bone marrow: An in vitro study. J Cell Physiol. 2018 Nov;233(11):8996-9006. doi: 10.1002/jcp.26845. Epub 2018 Jun 15. PubMed PMID: 29904927.

3: Alessio N, Squillaro T, Özcan S, Di Bernardo G, Venditti M, Melone M, Peluso G, Galderisi U. Stress and stem cells: adult Muse cells tolerate extensive genotoxic stimuli better than mesenchymal stromal cells. Oncotarget. 2018 Apr 10;9(27):19328-19341. doi: 10.18632/oncotarget.25039. eCollection 2018 Apr 10. PubMed PMID: 29721206; PubMed Central PMCID: PMC5922400.

4: Alessio N, Özcan S, Tatsumi K, Murat A, Peluso G, Dezawa M, Galderisi U. The secretome of MUSE cells contains factors that may play a role in regulation of stemness, apoptosis and immunomodulation. Cell Cycle. 2017 Jan 2;16(1):33-44. doi: 10.1080/15384101.2016.1211215. Epub 2016 Jul 27. PubMed PMID: 27463232; PubMed Central PMCID: PMC5270533.

5: Ozkul Y, Galderisi U. The Impact of Epigenetics on Mesenchymal Stem Cell Biology. J Cell Physiol. 2016 Nov;231(11):2393-401. doi: 10.1002/jcp.25371. Epub 2016 Apr 4. Review. PubMed PMID: 26960183.

6: Squillaro T, Peluso G, Galderisi U. Clinical Trials With Mesenchymal Stem Cells: An Update. Cell Transplant. 2016;25(5):829-48. doi: 10.3727/096368915X689622. Epub 2015 Sep 29. Review. PubMed PMID: 26423725.

7: Galderisi U, Giordano A. The gap between the physiological and therapeutic roles of mesenchymal stem cells. Med Res Rev. 2014 Sep;34(5):1100-26. doi: 10.1002/med.21322. Epub 2014 May 28. Review. PubMed PMID: 24866817.

8: Siniscalco D, Giordano A, Galderisi U. Novel insights in basic and applied stem cell therapy. J Cell Physiol. 2012 May;227(5):2283-6. doi: 10.1002/jcp.22945. PubMed PMID: 21780112.

9: Di Bernardo G, Alessio N, Dell'Aversana C, Casale F, Teti D, Cipollaro M, Altucci L, Galderisi U. Impact of histone deacetylase inhibitors SAHA and MS-275 on DNA repair pathways in human mesenchymal stem cells. J Cell Physiol. 2010 Nov;225(2):537-44. doi: 10.1002/jcp.22236. PubMed PMID: 20458754.

10: Di Bernardo G, Squillaro T, Dell'Aversana C, Miceli M, Cipollaro M, Cascino A, Altucci L, Galderisi U. Histone deacetylase inhibitors promote apoptosis and senescence in human mesenchymal stem cells. Stem Cells Dev. 2009 May;18(4):573-81. doi: 10.1089/scd.2008.0172. PubMed PMID: 18694296.