Tissue engineering and cell based therapies from the bench to the clinic: The potential to replace, repair and regenerate
Reprod Biol Endocrinol. 2003; 1: 102.
William L Fodor
The field of Regenerative Biology as it applies to Regenerative Medicine is an increasingly expanding area of research with hopes of providing therapeutic treatments for diseases and/or injuries that conventional medicines and even new biologic drug therapies cannot effectively treat. Extensive research in the area of Regenerative Medicine is focused on the development of cells, tissues and organs for the purpose of restoring function through transplantation. The general belief is that replacement, repair and restoration of function is best accomplished by cells, tissues or organs that can perform the appropriate physiologic/metabolic duties better than any mechanical device, recombinant protein therapeutic or chemical compound. Several strategies are currently being investigated and include, cell therapies derived from autologous primary cell isolates, cell therapies derived from established cell lines, cell therapies derived from a variety of stem cells, including bone marrow/mesenchymal stem cells, cord blood stem cells, embryonic stem cells, as well as cells tissues and organs from genetically modified animals.
1. Autologous Cell Therapy
Tissue specific differentiated autologous cells (as opposed to autologous progenitor cells, see below) harvested from an individual, cultured ex vivo to expand, and reintroduced into a second site for repairing damaged tissue with “self” is ideal from an immunologic perspective. Several pre-clinical models as well as clinical applications are currently being explored and include chondrocytes for cartilage repair, keratinocytes and/or dermal fibroblasts for burn and wound repair, myocytes for myocardial repair, retinal pigment epithelial cells for age related macular degeneration and Schwann cell transplantation to restore myelin in CNS lesions. The two most developed autologous cell therapies that have advanced from the laboratory to the clinic involve the repair of cartilage using autologous chondrocytes and the treatment of burns with autologous cultured keratinocytes.
Autologous progenitor cells harvested from an individual and used for “self” tissue repair is also immunologically ideal. The most widely used source of adult progenitor cells are derived from bone marrow.
Autologous peripheral blood or autologous bone marrow stem cells are currently used clinically.
2. Allogeneic Tissues and Cell Lines
The use of allogeneic tissue for transplantation is clinically routine due to the development of immunosuppressive drug therapies. The use of engineered tissue and specialized cell lines for the treatment of disease and injury is more recent and will also require immunosuppression unless engineering strategies are utilized to make the tissue resistant to immune destruction or through tissue processing to reduce immunogenicity. As is the case for autologous cell therapies, the furthest advances are in the area of connective tissue replacement, cartilage and skin. Currently, Apligraft® (Organogenesis, Inc) is used as a dermal replacement for chronic wounds and is composed of neonatal foreskin kerotinocytes and dermal fibroblasts. Although earlier studies demonstrated that Langerhan’s cell-free epidermal skin cultures were rejected following transplantation, Apligraft tissue appears to be uniquely non-immunogenic due to the processing of the tissue and represents an exception to the need for immunosuppression during allogeneic transplantation. A similar product, Dermagraft® is also available from Smith & Nephew.
Another interesting allogeneic cell type harvested from cadaveric sources for the treatment of Parkinson’s disease are allogeneic cultured retinal pigment epithelial cells that are encapsulated to provide an immune barrier.
3. Allogeneic stem cells
Allogeneic bone marrow transplantation is used clinically to treat hematologic disorders and cancer, but as is the case for autologous bone marrow transplantation, not from a commercial, tissue engineering standpoint. New clinical trials are focusing on the use of peripheral blood stem cells and specific subsets of bone marrow stem cells for these indications. The discovery and isolation of neural stem cells from fetal and adult human brain is a significant development in the area of neural cell differentiation that has led to the possibility of producing specialized cells for the treatment of neurologic disorders, such as Parkinson’s disease and spinal cord injury.
Although stem cells from adult tissues have more plasticity than originally thought, they typically are limited in their capacity to generate all possible tissue and cell types. Stem cells derived from the inner cell mass of the early embryonic blastocyst (ES cells) can proliferate indefinitely and can give rise to virtually any cell type. The development of human embryonic stem cells has raised the possibility that an unlimited supply of human tissue could be generated from ES cells and that these tissues could be used to replace and repair damaged tissue in any organ system.
4. Xenotransplantation
In the ongoing search for a reliable source of tissue to replace lost cells, tissues and organs, research in the area of xenotransplantation (cross species transplantation) has grown tremendously in the last 20 years. Overcoming the immunologic hurdle of cross species transplantation as well as the problem of cross-species pathogen infectivity, i.e., xenozoonosis, are the scientific challenges facing the field. The ability to genetically modify species such as the pig through transgenesis and nuclear transfer, to express human genes and to mutate detrimental genes expressed in pig cells still holds promise for engineered tissues and organs for human transplantation. The production of galα1,3gal transferase null transgenic pigs represents a significant development towards eliminating both hyperacute and acute vascular rejection and may lead to extended survival of pig organs in old world primates, including humans, in combination with standard triple drug immunosuppressive therapy.
Interestingly, there have been a series of pig-to-human xenotransplantation clinical experiments for the treatment of diabetes and FDA approved clinical trials for the treatment of neurologic disorders using outbred pig tissue. Although there was some evidence of cell engraftment in both indications, no efficacy was established due to the transplant. To date, a Phase I clinical trial was completed using transgenically engineered pig livers to detoxify the blood of fulminant hepatic failure (FHF) patients via extracoporial perfusion, however there is yet to be an FDA approved transgenic animal tissue for use in human transplantation.
Although the theoretical risk of xenozoonosis is a risk and represents a significant psychosocial issue, several studies investigating the possibility of cross species infectivity, including a retrospective analysis of 160 human transplant recipients exposed to porcine tissues have yet to reveal transmission of porcine viruses to humans or primates in vivo. The prospect of xenotransplantation is still relevant to solid organ and islet transplantation and with FDA oversight, animal as well as patient monitoring, the risks associated with xenozoonosis will be overcome.
