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Bone Marrow-derived Side Population Cells are Capable of Functional Cardiomyogenic Differentiation  

Yoon, Jihyun (Department of Cardiology, College of Medicine, Korea University)
Choi, Seung-Cheol (Department of Cardiology, College of Medicine, Korea University)
Park, Chi-Yeon (Department of Cardiology, College of Medicine, Korea University)
Choi, Ji-Hyun (Department of Cardiology, College of Medicine, Korea University)
Kim, Yang-In (Department of Physiology and Neuroscience Research Institute, College of Medicine, Korea University)
Shim, Wan-Joo (Department of Cardiology, College of Medicine, Korea University)
Lim, Do-Sun (Department of Cardiology, College of Medicine, Korea University)
Abstract
It has been reported that bone marrow (BM)-side population (SP) cells, with hematopoietic stem cell activity, can transdifferentiate into cardiomyocytes and contribute to myocardial repair. However, this has been questioned by recent studies showing that hematopoietic stem cells (HSCs) adopt a hematopoietic cell lineage in the ischemic myocardium. The present study was designed to investigate whether BM-SP cells can in fact transdifferentiate into functional cardiomyocytes. Phenotypically, BM-SP cells were $19.59%{\pm}9.00\;CD14^+$, $8.22%{\pm}2.72\;CD34^+$, $92.93%{\pm}2.68\;CD44^+$, $91.86%{\pm}4.07\;CD45^+$, $28.48%{\pm}2.24\;c-kit^+$, $71.09%{\pm}3.67\;Sca-1^+$. Expression of endothelial cell markers (CD31, Flk-1, Tie-2 and VEGF-A) was higher in BM-SP cells than whole BM cells. After five days of co-culture with neonatal cardiomyocytes, $7.2%{\pm}1.2$ of the BM-SP cells expressed sarcomeric ${\alpha}$-actinin as measured by flow cytometry. Moreover, BM-SP cells co-cultured on neonatal cardiomyocytes fixed to inhibit cell fusion also expressed sarcomeric ${\alpha}$-actinin. The co-cultured BM-SP cells showed neonatal cardiomyocyte-like action potentials of relatively long duration and shallow resting membrane potential. They also generated calcium transients with amplitude and duration similar to those of neonatal cardiomyocytes. These results show that BM-SP cells are capable of functional cardiomyogenic differentiation when co-cultured with neonatal cardiomyocytes.
Keywords
Bone Marrow; Cardiomyogenic Differentiation; Side Population Cells;
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1 Asakura, A., and Rudnicki, M.A. (2002). Side population cells from diverse adult tissues are capable of in vitro hematopoietic differentiation. Exp. Hematol. 30, 1339-1345   DOI   ScienceOn
2 Balsam, L.B., Wagers, A.J., Christensen, J.L., Kofidis, T., Weissman, I.L., and Robbins, R.C. (2004). Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature 428, 668-673   DOI   ScienceOn
3 Naylor, C.S., Jaworska, E., Branson, K., Embleton, M.J., and Chopra, R. (2005). Side population/ABCG2-positive cells represent a heterogeneous group of haemopoietic cells: implications for the use of adult stem cells in transplantation and plasticity protocols. Bone Marrow Transplant. 35, 353-360   DOI   ScienceOn
4 Ojima, K., Uezumi, A., Miyoshi, H., Masuda, S., Morita, Y., Fukase, A., Hattori, A., Nakauchi, H., Miyagoe-Suzuki, Y., and Takeda, S. (2004). Mac-1(low) early myeloid cells in the bone marrow-derived SP fraction migrate into injured skeletal muscle and participate in muscle regeneration. Biochem. Biophys. Res. Commun. 321, 1050-1061   DOI   ScienceOn
5 Wurmser, A.E., Nakashima, K., Summers, R.G., Toni, N., D'Amour, K.A., Lie, D.C., and Gage, F.H. (2004). Cell fusion-independent differentiation of neural stem cells to the endothelial lineage. Nature 430, 350-356   DOI   ScienceOn
6 Sanchez-Ramos, J.R. (2002). Neural cells derived from adult bone marrow and umbilical cord blood. J. Neurosci. Res. 69, 880-893   DOI   ScienceOn
7 Wojakowski, W., Tendera, M., Michalowska, A., Majka, M., Kucia, M., Maslankiewicz, K., Wyderka, R., Ochala, A., and Ratajczak, M.Z. (2004). Mobilization of CD34/$CXCR4^+$, CD34/$CD117^+$, c-$met^+$ stem cells, and mononuclear cells expressing early cardiac, muscle, and endothelial markers into peripheral blood in patients with acute myocardial infarction. Circulation 110, 3213-3220   DOI   ScienceOn
8 Goodell, M.A., Brose, K., Paradis, G., Conner, A.S., and Mulligan, R.C. (1996). Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J. Exp. Med. 183, 1797-1806   DOI   ScienceOn
9 Iijima, Y., Nagai, T., Mizukami, M., Matsuura, K., Ogura, T., Wada, H., Toko, H., Akazawa, H., Takano, H., Nakaya, H., et al. (2003). Beating is necessary for transdifferentiation of skeletal muscle-derived cells into cardiomyocytes. FASEB J. 17, 1361-1363   DOI
10 Pfister, O., Mouquet, F., Jain, M., Summer, R., Helmes, M., Fine, A., Colucci, W.S., and Liao, R. (2005). $CD31^-$ but Not $CD31^+$ cardiac side population cells exhibit functional cardiomyogenic differentiation. Circ. Res. 97, 52-61   DOI   ScienceOn
11 Labarge, M.A., and Blau, H.M. (2002). Biological progression from adult bone marrow to mononucleate stem cells to multinucleate muscle fiber in response to injury. Cell 111, 589-601   DOI   ScienceOn
12 Kucia, M., Reca, R., Jala, V.R., Dawn, B., Ratajczak, J., and Ratajczak, M.Z. (2005). Bone marrow as a home of heterogenous populations of nonhematopoietic stem cells. Leukemia 19, 1118-1127   DOI   ScienceOn
13 Petersen, B.E., Bowen, W.C., Patrene, K.D., Mars, W.M., Sullivan, A.K., Murase, N., Boggs, S.S., Greenberger, J.S., and Goff, J.P. (1999). Bone marrow as a potential source of hepatic oval cells. Science 284, 1168-1170   DOI   ScienceOn
14 Watt, F.M., and Hogan, B.L. (2000). Out of Eden: stem cells and their niches. Science 287, 1427-1430   DOI   ScienceOn
15 Lagostena, L., Avitabile, D., De Falco, E., Orlandi, A., Grassi, F., Iachininoto, M.G., Ragone, G., Fucile, S., Pompilio, G., Eusebi, F., et al. (2005). Electrophysiological properties of mouse bone marrow c-$kit^+$ cells co-cultured onto neonatal cardiac myocytes. Cardiovasc. Res. 66, 482-492   DOI   ScienceOn
16 Yoon, J., Shim, W.J., Ro, Y.M., and Lim, D.S. (2005). Transdifferentiation of mesenchymal stem cells into cardiomyocytes by direct cell-to-cell contact with neonatal cardiomyocyte but not adult cardiomyocytes. Ann. Hematol. 84, 715-721   DOI
17 Kajstura, J., Rota, M., Whang, B., Cascapera, S., Hosoda, T., Bearzi, C., Nurzynska, D., Kasahara, H., Zias, E., Bonafe, M., et al. (2005). Bone marrow cells differentiate in cardiac cell lineages after infarction independently of cell fusion. Circ. Res. 96, 127-137   DOI   ScienceOn
18 Laugwitz, K.L., Moretti, A., Lam, J., Gruber, P., Chen, Y., Woodard, S., Lin, L.Z., Cai, C.L., Lu, M.M., Reth, M., et al. (2005). Postnatal isl1+ cardioblasts enter fully differentiated cardiomyocyte lineages. Nature 433, 647-653   DOI   ScienceOn
19 Jackson, K.A., Majka, S.M., Wang, H., Pocius, J., Hartley, C.J., Majesky, M.W., Entman, M.L., Michael, L.H., Hirschi, K.K., and Goodell, M.A. (2001). Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J. Clin. Invest. 107, 1395-1402   DOI   ScienceOn
20 Kucia, M., Dawn, B., Hunt, G., Guo, Y., Wysoczynski, M., Majka, M., Ratajczak, J., Rezzoug, F., Ildstad, S.T., Bolli, R., et al. (2004). Cells expressing early cardiac markers reside in the bone marrow and are mobilized into the peripheral blood after myocardial infarction. Circ. Res. 95, 1191-1199   DOI   ScienceOn
21 Lee, V.M., and Stoffel, M. (2003). Bone marrow: an extrapancreatic hideout for the elusive pancreatic stem cells? J. Clin. Invest. 111, 799-801   DOI
22 Storms, R.W., Goodell, M.A., Fisher, A., Mulligan, R.C., and Smith, C. (2000). Hoechst dye efflux reveals a novel CD7(+)CD34(-) lymphoid progenitor in human umbilical cord blood. Blood 96, 2125-2133
23 Montanaro, F., Liadaki, K., Schienda, J., Flint, A., Gussoni, E., and Kunkel, L.M. (2004). Demystifying SP cell purification: viability, yield, and phenotype are defined by isolation parameters. Exp. Cell Res. 298, 144-154   DOI   ScienceOn
24 Murry, C.E., Soonpaa, M.H., Reinecke, H., Nakajima, H., Nakajima, H.O., Rubart, M., Pasumarthi, K.B., Virag, J.I., Bartelmez, S.H., Poppa, V., et al. (2004). Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature 428, 664-668   DOI   ScienceOn
25 Parmar, K., Sauk-Schubert, C., Burdick, D., Handley, M., and Mauch, P. (2003). Sca+CD34- murine side population cells are highly enriched for primitive stem cells. Exp. Hematol. 31, 244-250   DOI   ScienceOn
26 Yao, A., Su, Z., Nonaka, A., Zubair, I., Spitzer, K.W., Bridge, J.H., Muelheims, G., Ross, J.Jr., and Barry, W.H. (1998). Abnormal myocyte $Ca^2+$ homeostasis in rabbits with pacing induced heart failure. Am. J. Physiol. 275, H1441-H1448
27 Terada, N., Hamazaki, T., Oka, M., Hoki, M., Mastalerz, D.M., Nakano, Y., Meyer, E.M., Morel, L., Petersen, B.E., and Scott, E.W. (2002). Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature 416, 542-545   DOI   ScienceOn
28 Fraser, A.R., Cook, G., Franklin, I.M., Templeton, J.G., Campbell, M., Holyoake, T.L., and Campbell, J.D. (2006). Immature monocytes from G-CSF-mobilized peripheral blood stem cell collections carry surface-bound IL-10 and have the potential to modulate alloreactivity. J. Leukoc. Biol. 80, 862-869   DOI   ScienceOn
29 Goodell, M.A., Rosenzweig, M., Kim, H., Marks, D.F., De- Maria, M., Paradis, G., Grupp, S.A., Sieff, C.A., Mulligan, R.C., and Johnson, R.P. (1997). Dye efflux studies suggest that hematopoietic stem cells expressing low or undetectable levels of CD34 antigen exist in multiple species. Nat. Med. 3, 1337-1345   DOI   ScienceOn
30 Sales-Pardo, I., Avendano, A., Martinez-Munoz, V., Garcia-Escarp, M., Celis, R., Whittle, P., Barquinero, J., Domingo, J.C., Marin, P., and Petriz, J. (2006). Flow cytometry of the side population: tips & tricks. Cell Oncol. 28, 37-53
31 Nygren, J.M., Jovinge, S., Breitbach, M., Sawen, P., Roll, W., Hescheler, J., Taneera, J., Fleischmann, B.K., and Jacobsen, S.E. (2004). Bone marrow-derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation. Nat. Med. 10, 494-501   DOI   ScienceOn