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Adult Stem Cells: Hopes and Hypes of Regenerative Medicine* Józef Dulak*, Krzysztof Szade, Agata Szade, Witold Nowak and Alicja Józkowicz

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Adult Stem Cells: Hopes and Hypes of Regenerative Medicine* Józef Dulak*, Krzysztof Szade, Agata Szade, Witold Nowak and Alicja Józkowicz Vol. 62, No 3/2015 329–337 http://dx.doi.org/10.18388/abp.2015_1023 Review Adult stem cells: hopes and hypes of regenerative medicine* Józef Dulak*, Krzysztof Szade, Agata Szade, Witold Nowak and Alicja Józkowicz Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland Stem cells are self-renewing cells that can differentiate The examples of pluripotent stem cell are embryon- into specialized cell type(s). Pluripotent stem cells, i.e. ic stem cells (ESC) and induced pluripotent stem cells embryonic stem cells (ESC) or induced pluripotent stem (iPSC) (Takahashi & Yamanaka, 2006). cells (iPSC) differentiate into cells of all three embryonic Adult stem cells, which exist in the postnatal organ- lineages. Multipotent stem cells, like hematopoietic stem ism, are either multipotent or unipotent (Wagers & cells (HSC), can develop into multiple specialized cells in Weissman, 2004). The majority of known adult stem a specific tissue. Unipotent cells differentiate only into cells reside in the bone marrow. Among them are the one cell type, like e.g. satellite cells of skeletal muscle. multipotent HSC which have a capacity to regenerate There are many examples of successful clinical applica- the entire hematopoietic system (Bryder et al., 2006). Ac- tions of stem cells. Over million patients worldwide have cordingly, therapeutic bone marrow transplantation has benefited from bone marrow transplantations performed been used for more than 30 years, and more than mil- for treatment of leukemias, anemias or immunodeficien- lion patients suffering from different blood diseases have cies. Skin stem cells are used to heal severe burns, while already been treated with transplantation of the BM or limbal stem cells can regenerate the damaged cornea. the mobilized BM-derived cells. The other adult stem Pluripotent stem cells, especially the patient–specific cells that reside in the bone marrow are the mesenchy- iPSC, have a tremendous therapeutic potential, but their mal stem cells, defined also as the mesenchymal stromal clinical application will require overcoming numerous cells (MSC), which can differentiate into the bone, chon- drawbacks. Therefore, the use of adult stem cells, which drocytes and adipose cells (Bianco, 2014) (Fig. 1). are multipotent or unipotent, can be at present a more achievable strategy. Noteworthy, some studies ascribed IN THE SEARCH FOR PLURIPOTENT ADULT STEM CELL particular adult stem cells as pluripotent. However, de- spite efforts, the postulated pluripotency of such events like “spore–like cells”, “very small embryonic-like stem Multipotent or unipotent differentiation potential of cells” or “multipotent adult progenitor cells” have not adult bone marrow stem cells, like HSC or MSC, are been confirmed in stringent independent studies. Also very well known. Nevertheless, from time to time, it is plasticity of the bone marrow–derived cells which were claimed that the bone marrow cells can give rise to the suggested to differentiate e.g. into cardiomyocytes, has cells of various organs and can differentiate not only not been positively verified, and their therapeutic effect, into the blood or to the bone, but also to the blood ves- if observed, results rather from the paracrine activity. sels (Asahara et al., 1999), muscles (Ferrari et al., 1998), Here we discuss the examples of recent studies on adult cardiomyocytes (Orlic et al., 2001), skin (Kataoka et al., stem cells in the light of current understanding of stem 2003) or even can regenerate the kidney (Kale et al., cell biology. 2003), pancreas (Hess et al., 2003) and the nervous sys- tem (Mezey et al., 2000). What are the scientific ration- Key words: embryonic stem cells, induced pluripotent stem cells, ales and proofs underlying such conclusions? myocardial infarction, very small embryonic–like stem cells, heme The vast differentiation potential of the bone marrow- oxygenase–1 derived cells has often been suggested on the basis of Received: 07 April, 2015; revised: 26 April, 2015; accepted: 02 May, experiments performed in cells cultured for the long 2015; available on-line: 22 July, 2015 time in vitro. Indeed, under such conditions, the expres- sion of different markers can be demonstrated in the bone marrow cells. Recently our group has investigated DEFINITION OF STEM AND PROGENITOR CELL the murine bone marrow-derived mesenchymal cells with CD45–CD34+CD14+ phenotype (Szade et al., 2011). To isolate this population we cultured plastic adherent bone Stem cell is an undifferentiated cell, which can self– marrow cells for at least 10 passages. During this long- renew to replicate itself as well as give rise to the spe- term culture the cells changed considerably their gene cialized cells under appropriate conditions (Weissman, 2000). Progenitor cell lacks the self–renewal capability *e-mail: [email protected] and often is unipotent — differentiates into only one *Presented at 42nd Winter School of the Faculty of Biochemistry, cell type. Biophysics and Biotechnology of the Jagiellonian University, Febru- There are distinct kinds of stem cells according to ary 16–21, 2015, Zakopane, Poland. their differentiation potential. Multipotent stem cells can Abbreviations: CO, carbon monoxide; ESC, embryonic stem cells; differentiate into many cell types, but within a particular GFP, green fluorescent protein; HO-1, Heme oxygenase-1; HSC, he- lineage. For example, the hematopoietic stem cells (HSC) matopoietic stem cells; iPSC, pluripotent stem cells; MAPC, multi- can develop into red blood cells, white blood cells and potent adult progenitor cells; LAD, left anterior descending; LVEF, platelets. Pluripotent stem cells are capable of giving rise left ventricular ejection fraction to all cells of all tissue types (Jaenisch & Young, 2008). 330 J. Dulak and others 2015 Figure 1. Major properties of stem cells. Pluripotent stem cells under normal circumstances are not present in the adult organism — they are obtained as the result of isolation of the inner cell mass of the blastocyst (embryonic stem cells) or reprogramming of somatic cells by overexpression of defined transcrip- tion factors (induced pluripotent stem cells). Adult stem cells are either multipotent or unipotent. In the same organ, e.g. in the skin, both multipotent and unipotent populations of stem cells can exist. expression profile (Szade et al., 2011). Such cultured al., 2014) and others (Deramaudt et al., 1998; Bussola- population could differentiate into PPARγ+ adipocytes, ti et al., 2004; Lakkisto et al., 2011) to play a protective what reflected the natural propensity of MSC. Under role in cardiovascular system. The HO-1 activation can conditions promoting endothelial cell growth, we ob- be cytoprotective, anti-apoptotic, anti-inflammatory and served upregulation of endothelial genes and some en- proangiogenic. HO-1 overexpression in the heart reduc- dothelial function properties, like formation of tube-like es the cardiomyocyte death and fibrosis, improving the structures on Matrigel, lectin binding or upregulation of myocardial functions and preventing damages caused by VCAM-1 after TNFα stimulation. On the other hand, the myocardial ischemia. The expression of HO-1 can be under neuronal differentiation conditions a few cells of diminished under various pathological conditions; hence this population expressed the neuronal markers (Szade et its upregulation is considered to be of therapeutic ben- al., 2011). efit (reviewed in Dulak et al., 2008). Accordingly, several Expression of different markers appearing in the studies have previously demonstrated that application of in vitro cultures of bone marrow cells is considered as bone marrow-derived mesenchymal cells overexpressing an indication of their vide differentiation potential and HO-1 improved the function of the ischemic murine makes the rationale for application of such cells for the heart (Tang et al., 2005). In line with those results we treatment of various conditions in organs in which the used porcine bone marrow cells for treatment of myo- bone marrow cells do not reside naturally. Accordingly, cardial infarction in pigs (Wojakowski et al., 2012). To the bone marrow cells have been used in experimental improve the properties of the isolated cells we trans- animals for treatment of myocardial infarction (Kamihata duced them with adenoviral vectors harboring HO-1. et al., 2001; Orlic et al., 2001), hind limb ischemia (Kalka Control cells were transduced with vectors encoding et al., 2000), stroke (Chen et al., 2001), as well as liver green fluorescent protein (GFP). In vitro observations (Petersen et al., 1999) or kidney injury (Kale et al., 2003). showed that the mesenchymal cells engineered to over- It has been claimed that the bone marrow cells have the express HO-1 formed better tube-like structures than capacity to differentiate into cardiomyocytes (Orlic et al., their GFP expressing counterparts, what might indicate 2001), endothelial cells (Asahara et al., 1997), neuronal that HO-1 improves their angiogenic capacity (Woja- cells (Mezey et al., 2000), hepatocytes (Petersen et al., kowski et al., 2012). 1999) or kidney epithelial cells (Kale et al., 2003). Par- Such cells were used in pigs subjected to experimental ticularly the bone marrow MSC were regarded as cells of myocardial infarction caused by occlusion of left anterior versatile properties (Jiang et al., 2002). Soon after the ex- descending (LAD) artery by means of the balloon cath- perimental
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