Introduction Stroke remains a leading cause of adult disabil
Stroke remains a leading cause of adult disability worldwide. In Brazil it is the leading cause of death, with a mortality rate of approximately 51.6 deaths per 100,000 inhabitants (Garcia et al., 2009) and shows the highest case-fatality rate in Latin America (Lotufo and Bensenor, 2009). Recently, cell-based therapies have emerged as a promising tool for the treatment of stroke (Baker et al., 2007; Hicks et al., 2009; Lindvall and Kokaia, 2010; Ohtaki et al., 2008; Shimada and Spees, 2011) and different cell types and routes have been used in these studies. In order to be able to translate these results to a clinical setting, more information is required regarding the safety and efficacy of the different cell types, doses, and routes of administration. Therapy with BMMCs has led to functional improvement in animal models of focal cerebral ischemia when the cells were transplanted either intravenously or intra-arterially (Brenneman et al., 2010; de Vasconcelos Dos Santos et al., 2010; Giraldi-Guimaraes et al., 2009; Iihoshi et al., 2004; Nakano-Doi et al., 2010). Independent of the delivery route, several studies using labeled cells from different tissues and species donors suggest the existence of a high rate of cell entrapment in peripheral organs (Detante et al., 2009; Fischer et al., 2009; Gao et al., 2001). Moreover, the number of injected cells reaching the topotecan Supplier parenchyma seems to be small (Detante et al., 2009; Lappalainen et al., 2008). Despite the small number of cells found in the brain tissue, functional effects have been observed in the cell-treated animals, suggesting that peripheral mechanisms may play a systemic role in cell therapy, i.e., the cells do not necessarily need to reach the central nervous system in order to trigger their therapeutic effects (Borlongan et al., 2004; Mendez-Otero et al., 2007). In this respect, a careful evaluation of the biodistribution of the transplanted cells and a correlation with the functional efficacy may provide a better understanding of the mechanisms involved in the therapeutic effects observed. Nuclear Medicine techniques provide valuable means for monitoring cell therapies in vivo, with high image quality. In addition, these techniques also allow us to estimate the number of cells in different organs and tissues by counting the activity in the isolated organs (Detante et al., 2009; Lassance et al., 2009; Quintanilha et al., 2008). Our working hypothesis is that the effect of BMMCs may not depend on the intravascular modality of administration. Therefore, the present study examined the therapeutic effect after IV and IA administrations of BMMCs. We also investigated the distribution of these cells, to determine whether there are differences in effectiveness between these routes of administration.
Conclusions To our knowledge, this is the first study to compare IA and IV routes of administration of BMMCs for the therapy of cortical ischemia, produced in a model of thermocoagulation, in terms of biodistribution and efficacy. Twenty-four hours after cell transplantation, homing in the brain seems to be comparable between both routes in ischemic animals as analyzed by 99mTc and CellTrace labeling, and greater than that of non-ischemic animals. Moreover, the functional studies indicate a similar recovery of the sensorimotor function, as evaluated by the cylinder test, up to 11weeks post-ischemia after IV or IA BMMC therapy.
Material and methods
Introduction An integrated ocular surface is composed of a healthy precorneal tear film and the intact corneal, conjunctival as well as the limbal epithelia. The homeostasis of the corneal epithelial cells is maintained by their stem cells (SCs), which are located at the limbal zone (Schermer et al., 1986). Limbal stem cell deficiency (LSCD), which may be caused by chemical and thermal burns, Stevens-Johnson syndrome, repetitive ocular surgeries or other conditions, is manifested clinically by chronic inflammation, corneal neovascularization, and loss of vision (Holland and Schwartz, 1996). Therefore, restoration of the SC population is a prerequisite to obtain a stable ocular surface and is required for a subsequently successful corneal transplantation (Sangwan et al., 2005). By the concepts and applications of limbal epithelial SCs, such patients, especially those with total LSCD, were treated either by transplantation of one or more segments of limbal tissue (Kenyon and Tseng, 1989) or by transplantation of ex vivo cultivation of limbus-derived epithelial cells on amniotic membranes (AM) (Tsai et al., 2000). Currently, the latter is thought to be superior to the former, which may escape from the incidence of allograft rejection and the potential risk of LSCD to the donor eye (Lavker et al., 2004). To date, such ex vivo-expanded limbal epithelial cells on AM have been successfully transplanted for reconstructing the corneal surface in patients suffering from total LSCD (Tsai et al., 2000).