Multiple cell sources have been considered for cardiovascular cell therapy. These sources range from autologous (derived from the patient’s own tissues) to allogeneic (not from self). Other articles in this issue and previous reviews compare and contrast these sources.[5
] We will focus on the practical and ethical issues associated with the different cell sources. It is essential to appreciate that the complexity of living cells is tremendous and that understanding the detailed phenotypic properties of a cell preparation is a far greater challenge than characterizing the chemical properties and purity of a pharmaceutical agent.
Autologous cell sources have generally undergone the most rapid translation to clinical trials in part based on limited concern about immune rejection and decades of experience with bone marrow transplantation. Initial trials have varied tremendously in the processing and selection of cells from simply isolating a mononuclear fraction from bone marrow cells and rapidly delivering them back to the heart to isolation of myoblasts from a muscle biopsy followed by several weeks of culture expansion before delivery.[2
] If there is limited processing of cells, then the possibility for unanticipated events appears to be minimal. However, the more the autologous cells are processed and/or expanded, the greater the likelihood of potential problems including microbial contamination, aberrant cellular phenotypes, and tumorigenicity. Another complicating factor is that autologous cells can vary tremendously from patient to patient. Significant variation in progenitor cell availability among adults with coronary artery disease exists,[9
] and the functional ability of the cells can vary between a healthy normal volunteer and, for example, a patient with diabetes and severe systemic atherosclerosis.[10
] Autologous cell sources used to date have generated little in the way of ethical concerns and have not been the subject of major public policy debate.
Allogeneic cell sources are also actively being investigated. Mesenchymal stem cells (MSCs) obtained from bone marrow can be greatly expanded in culture and allogeneic MSCs are being tested in a Phase I clinical trial post-MI. MSCs are obtained from adult tissues and have raised few ethical concerns, in contrast to the other major sources of allogeneic stem cells under investigation such as embryonic stem cells (ESCs). Wide application of allogeneic cell therapy may be limited by institutional variability in cell processing, expense and reduced viability due to prolonged storage, and immune rejection.
ESCs are cells derived from the inner cell mass of the preimplantation blastocysts, which are very early stage embryos. These blastocysts may come from surplus, unused embryos created for in vitro
fertilization procedures. Most often these are frozen, stored embryos, and are obtained with informed consent of the embryo donors with the stated purpose of being used for research.1
However, derivation of the ESCs results in destruction of the embryo which raises ethical concerns regarding:
- The moral status of early forms of life (embryos)
- Taxpayer complicity in funding the destruction of early embryos
- The protection of human subjects, which for some people includes the embryo
- Research and academic freedoms to pursue research deemed to have merit
- Protections and rights of donors of gamete tissue or embryos
A wide diversity of opinions exists regarding these fundamental questions, which has resulted in highly divergent research policies around the world. The inner cell mass of the preimplantation blastocysts used for isolation of human ESC lines contains only undifferentiated, pluripotent cells that have not begun the process of organogenesis. No neural cells are present in the inner cell mass and thus there is no form of consciousness. Opponents of human ESC research argue that these embryos have genetic completeness and the potential to develop into a child, and these properties afford embryos the same moral status and legal protections as any human being. Proponents of human ESC research counter that all cells in the body have genetic completeness yet are not given such status. For example, somatic cell nuclear transfer, in which a nucleus from a fibroblast or other somatic cell can be transferred to an enucleated oocyte to create ESCs, challenges notions that developmental potential is specific to blastocysts. Arguments about potentiality have been central to debates about the moral status of embryos, and have led some to propose alternative derivation techniques intended to circumvent the possibility that a blastocyst from which cells are derived could have further developed into a human.[11
Additionally, derivation of human ESCs from a single blastomere biopsy without destroying the embryo has been suggested as another strategy to isolate ethically acceptable human ESC lines.[14
] However, this argument assumes that a single blastomere is not capable of generating a viable embryo, but this is not the case for certain species and unknown for humans.[15
] Thus the question remains as to what pluripotent cells if any require special status and protection. For example, recent studies have demonstrated that overexpression of several specific genes in mouse fibroblasts can result in generation of pluripotent stem cells that share many properties of ESCs including the ability to form chimeric animals when injected into a blastocyst.[16
] Additionally, stem cell lines have been isolated from mouse spermatagonial stem cells which share many features of ESCs.[18
] The moral status of the embryo and pluripotent stem cells will continue to be the subject of debate, and will have a significant effect on political, legislative and funding decisions .[19
] Readers are referred to extensive discussions in other sources (see )
Additional online resources regarding ethics, regulation, and policy of human ESC research