Electronic Journal of Biotechnology Universidad Católica de Valparaíso ISSN: 0717-3458 Vol. 5, Num. 3, 2002

Electronic Journal of Biotechnology, Vol. 5, No. 2, August, 2002

EDITORIAL

Cell transplant therapy: What, when, where...

Pablo A. Caviedes

Program of Molecular and Clinical Pharmacology, ICBM, Faculty of Medicine, University of Chile, Casilla 70000, Correo 7, Santiago, Chile Tel: 562 678 6559 (voice) Fax: 562-737 2783 pcaviede@machi.med.uchile.cl

Code Number: ej02030

The use of cell transplantation has been proposed as a therapeutical possibility for several illnesses, which share loss of cell number and/or function as a feature. The aim of this therapy is to replace damaged tissue or provide protection against damaging mechanisms. To this day, great efforts have been undertaken in the development of such therapies in neurodegenerative disorders such as Parkinson's disease, and also in myocardial infarction and type 1 diabetes. However, success in cell transplant therapy has been hampered by problems such as cell availability, cell mass and stage of differentiation. In this regard, current sources are difficult to access and are inherently hampered by ethical, practical and cultural considerations, which is the case of human fetal tissue and embryonic stem cells. Further, viability after transplantation of fetal tissue is low (approximately 5% of cells survive), and clinical trials have yielded great variability. Stem cells, although potentially attractive candidates due to their totipotentiality, have several inherent obstacles other than their origin, such as 1) slow proliferation in vitro, 2) complex and expensive differentiation treatments to obtain the required cell types, 3) safety risks associated with transplantation of undifferentiated, migratory stem cells and 4) tumour formation in some stem cell lines. Other sources, such as adult blood and bone marrow, have an aging problem inherent to the "biological clock" of the cells from such donors. Finally, xenografts with cells of porcine origin have yielded somewhat disappointing results, and they must also be associated with permanent immunosuppressive therapy and carry the risk of potential infections with porcine viruses.

In Parkinson's disease, we can consider two advantages for cell transplantation therapy: 1) the discrete anatomical localization of the degenerating tissue, and 2) the immunoprivileged condition of the CNS. However, to the problems previously stated, long-term graft survival appears as yet another hurdle to overcome; as when dopaminergic neurons from the substantia nigra are implanted in patients at an anatomical site, the striatum, where the immediate microenvironment does not know of such neurons. Indeed, the extracellular matrix in the striatum may very well be quite different from that of the substantia nigra or of the origin of whichever cell type is being implanted; and signaling molecules embedded in this matrix may condition implanted cells to change their phenotype to that of striatal cells; or, simply the lack of the correct trophic factors or stimuli renders the environment inhabitable for the graft.

All these considerations, along with the current worldwide economical situation, tend to discourage a large commitment of the private sector in such technologies. Such commitment is essential considering the necessary regulatory frame governing clinical trials in cell transplant therapy, which demand lengthy and costly tests and protocols.

The development of new procedures to enhance proliferation and differentiation in vitro of stem or progenitor cells is important, yet it may result insufficient to satisfy the demands. Therefore, the procurement for new, unlimited cell sources is a greatly desirable goal. In this regard, the use of immortalized cell lines appears as a very attractive possibility in cell transplant therapy. They could provide an endless supply of tissue readily accessible for modulation in vitro prior to transplant. In this regard, human cell lines of non-neuronal origin, such as the testicular teratocarcinoma- derived NT2 cells, have already been used in neuronal cell transplant. This cell line, when cultured in the presence of retinoic acid for several weeks, differentiates into post-mitotic neurons (also called NT2N cells or LBS neurons). This, and the use of human neural stem cells, are the most recent cell types with potential clinical use, and could contribute in offering another therapeutic alternative, although a number of technical issues must still be addressed before this form of therapy can become standard.