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Tissue engineering and cell based therapies, from the bench to the clinic: The potential to replace, repair and regenerate


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. This mini-review is not meant to be exhaustive, but aims to highlight clinical applications for the four areas of research listed above and will address a few key advances and a few of the hurdles yet to be overcome as the technology and science improve the likelihood that Regenerative Medicine will become clinically routine.


Many diseases and or physical defects due to injury result in the loss of specialized cells within organ systems and lead to organ system dysfunction. For example, Parkinson's disease results in the progressive loss of dopaminergic neurons within the substantia nigra region of the brain leading to motor deficits that result in dystonia and dyskinesia. Injuries, such as meniscal tears and spinal cord injury, can also result in the degeneration and loss of tissue leading to physical defects that can affect normal behavior. Additionally, insulin dependant diabetes mellitus (IDDM), multiple sclerosis (MS) and other autoimmune disorders lead to a loss of tissue that disrupts normal metabolism and bodily functions. The potential to treat these conditions with cell-based therapies holds promise for tissue/organ repair with the ultimate goal to regenerate and restore normal function. Several cell types will be discussed and are defined as; tissue specific differentiated cells, such as chondrocytes; progenitor cells isolated from specific tissues, such as bone marrow stem cells or neural stem cells; and embryonic stem cells that are derived from the inner cell mass of the developing blastomere.

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 [112], keratinocytes and/or dermal fibroblasts for burn and wound repair [1317], myocytes for myocardial repair [1823], retinal pigment epithelial cells for age related macular degeneration [2427] and Schwann cell transplantation to restore myelin in CNS lesions. [2832]. 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.

Grande et. al., first demonstrated that autologous chondrocyte cultures could be utilized to repair articular cartilage defects in the rabbit knee [11, 12]. Subsequently, this technique has been applied to the clinical treatment of articular cartilage defects [1, 4, 7, 33] and has now evolved into an FDA approved therapy supplied by Genzyme Biosurgery Genzyme Biosurgery has also developed an autologous keratinocyte culture procedure and currently markets Epicel® as a treatment for burn victims Although repairing "self" with "self" is attractive and doesn't require immunosuppressive drug therapy for graft maintenance, there are limitations related to the harvesting of tissue and expanded tissue culture. Typically, harvesting the original source tissue from the patient requires a surgical procedure which minimally is a biopsy, but could also require a large resection of the tissue. The concern is causing a second site defect that leads to pain, discomfort or a deficit that effects behavior, hopefully to a lesser extent than the original. The ability of the adult tissue to expand in tissue culture to generate sufficient numbers of cells is also a potential limitation. Additionally, primary cell cultures can become senescent or dedifferentiate during the culture period. Another limitation is that this type of therapy is only amenable to tissues that can sustain surgical harvesting and ex vivo culturing, emphasized by the fact that only two autologous cell therapies have achieved FDA approval for the medical market.

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. The mesenchymal compartment within the bone marrow has the capacity to differentiate into many cell and tissue types given the appropriate growth conditions [34]. Early studies using bone marrow stromal cells for tissue repair focused on the repair of bone defects [35] however, more recent studies have applied bone marrow progenitor cells to repair a variety damaged tissue types, including cartilage [3638], myocardium [39, 40], liver [41], spinal cord injury [4244] and most recently diabetes [45]. However, these differentiation studies are still in the experimental stage. The potential to differentiate "self" progenitor cells into a variety of tissues is extremely promising for the field of Regenerative Medicine, however continued experimentation is necessary to understand the differentiation processes and to be able to reproducibly guide these cells into the appropriate tissue, prior to clinical application.

Autologous peripheral blood or autologous bone marrow stem cells are currently used clinically, but not from a commercial stand point. A current search of the FDA web site resulted in 108 studies involving autologous peripheral blood or autologous bone marrow stem cells as a treatment therapy, 96 of which were related to cancer treatments. None of the trials are related to stem cell differentiation followed by transplantation.

Allogeneic Tissues and Cell Lines

The use of allogeneic tissue for transplantation is clinically routine due to the development of immunosuppressive drug therapies, such as cyclosporine, FK506 and rapamycin. 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. [4648] Currently, Apligraft® (Organogenesis, Inc) is used as a dermal replacement for chronic wounds and is composed of neonatal foreskin kerotinocytes and dermal fibroblasts [49]. Although earlier studies demonstrated that Langerhan's cell-free epidermal skin cultures were rejected following transplantation [50], Apligraft tissue appears to be uniquely non-immunogenic due to the processing of the tissue [51, 52] 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 [53]. Titan Pharmaceuticals, Inc has advanced this research into the clinic and is currently conducting a Phase IIb clinical trial with initial positive results [54].

Allogeneic cell lines are also being developed as a source of cells for regenerating damaged tissue due to disease. The human NT2 cell line was shown to differentiate and develop into neurons in rodent stroke models [55, 56] and is currently being tested in clinical trials for the treatment of stroke by Layton Biosciences, Inc [57, 58]. Patients receiving the NT2 cell grafts do receive immunosuppression to inhibit immune rejection of the graft [57, 58].

The development of allogeneic engineered tissues for commercial purposes has similar limitations as commercial autologous cell therapies with the added complication of immune rejection. Encapsulation, tissue processing, tolerance induction and/or genetic modification will be necessary unless the patient population is receptive to and the severity of the disease warrants the use of immunosuppressive drugs.

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 (for example [59, 60]). Searching the FDA clinical trial data base identified 117 trials that utilize allogeneic stem cells or bone marrow in the treatment regime. Sorting through those trials, 99 were specific for stem cell therapy. As for autologous bone marrow or peripheral blood stem cell therapies, most were for cancer indications, 84/99. The data base included 9 trials utilizing allogeneic stem cells for anemia/hematologic disorders, 2 trials are designed to treat metabolic storage diseases and there are single trials for each of the following; Granulomatous Disease, HIV patients not responsive to highly active antiretroviral therapy, Mycosis Fungoides and Sezary Syndrome and allogeneic bone marrow rejection Virtually all of these therapies are in combination with some form of immunosuppression and none of the trials are related to stem cell differentiation followed by transplantation.

The discovery and isolation of neural stem cells from fetal [6164] and adult human brain [65, 66] 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. Many groups have studied the differentiation of neurospheres into neuron, glial, and astrocyte lineages, however the work from Goldman's group [66, 67] sets a president for selection strategies that are most relevant to the field of tissue engineering. Nunes, et. al., and Keyoung et. al., showed that transfected/transduced specific promoter constructs driving green fluorescent protein (GFP) can be used to select specific neural progenitor cells by flow cytometry [66, 67]. Expanding on these techniques could lead to the eventual development of a commercial application of neural stem cells by reproducibly selecting the desired neural phenotype. Demonstrating that specific lineages can be selected genetically with drug selectable or fluorescent expression plasmids lays the ground work for further selection schemes and further genetic modifications, such as modifying the immune response leading to a universally accepted source of human neural tissue for transplantation.

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 [68] and can give rise to virtually any cell type [69]. The development of human embryonic stem cells [70] 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. It should be noted that although these human cells are referred to as ES cells, they cannot be qualified as a true "ES cell" which is defined by the ability to contribute to the germ line during embryonic development. ES cells from other species are tested in this manner, however it is ethically unfeasible with human ES cells. Having qualified the definition of a human ES cell, several studies have demonstrated that human ES cells retain the capacity to differentiate into a variety of tissues, including neuronal cells, myocytes, adipocytes and hematopoietic cells [7177]. The challenge now is to be able to direct differentiation or select for the desired phenotype and to develop these therapies in the absence of immunosuppression, similar to the strategies taken by the field of xenotransplantation. The ability to genetically modify ES cells is a great advantage and could be used to overcome both the directed differentiation/selection hurdle as well as the immune response hurdle.


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 [78, 79]. 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 [8086] still holds promise for engineered tissues and organs for human transplantation. The production of galα1,3gal transferase null transgenic pigs [84] 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 [87, 88] and FDA approved clinical trials for the treatment of neurologic disorders using outbred pig tissue [8991]. Although there was some evidence of cell engraftment in both indications [87, 90], no efficacy was established due to the transplant [87, 89]. 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 [92], 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 [9396]. 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.

The Future

The challenges associated with stem cell differentiation, tissue engineering, and xenotransplantation are many-fold in each of the respective fields, however one of the biggest challenges beyond the science and biology is the development of an FDA approved product from any of the developmental areas discussed above. The regulatory issues and points to consider documents are in the early stages of development by the FDA in collaboration with expert review panels and will continue to change as the technology advances into clinical applications. The experiences of Genzyme Biosurgery, Organogenesis, Diacrin, Layton Biosciences, Titan Pharmaceuticals and other tissue engineering companies will benefit the field as a whole.


  1. 1.

    Brittberg M, Lindahl A, Nilsson A, Ohlsson C, Isaksson O, Peterson L: Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med. 1994, 331: 889-895. 10.1056/NEJM199410063311401.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Brittberg M, Nilsson A, Lindahl A, Ohlsson C, Peterson L: Rabbit articular cartilage defects treated with autologous cultured chondrocytes. Clin Orthop. 1996, 270-283. 10.1097/00003086-199605000-00034.

    Google Scholar 

  3. 3.

    Minas T: Chondrocyte implantation in the repair of chondral lesions of the knee: economics and quality of life. Am J Orthop. 1998, 27: 739-744.

    CAS  PubMed  Google Scholar 

  4. 4.

    Brittberg M: Autologous chondrocyte transplantation. Clin Orthop. 1999, S147-55. 10.1097/00003086-199910001-00016.

    Google Scholar 

  5. 5.

    Minas T, Peterson L: Advanced techniques in autologous chondrocyte transplantation. Clin Sports Med. 1999, 18: 13-44, v-vi.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Robinson D, Ash H, Aviezer D, Agar G, Halperin N, Nevo Z: Autologous chondrocyte transplantation for reconstruction of isolated joint defects: the Assaf Harofeh experience. Isr Med Assoc J. 2000, 2: 290-295.

    CAS  PubMed  Google Scholar 

  7. 7.

    Brittberg M, Tallheden T, Sjogren-Jansson B, Lindahl A, Peterson L: Autologous chondrocytes used for articular cartilage repair: an update. Clin Orthop. 2001, S337-48.

    Google Scholar 

  8. 8.

    King PJ, Bryant T, Minas T: Autologous chondrocyte implantation for chondral defects of the knee: indications and technique. J Knee Surg. 2002, 15: 177-184.

    PubMed  Google Scholar 

  9. 9.

    Peterson L, Brittberg M, Kiviranta I, Akerlund EL, Lindahl A: Autologous chondrocyte transplantation. Biomechanics and long-term durability. Am J Sports Med. 2002, 30: 2-12.

    PubMed  Google Scholar 

  10. 10.

    Peterson L, Minas T, Brittberg M, Lindahl A: Treatment of osteochondritis dissecans of the knee with autologous chondrocyte transplantation: results at two to ten years. J Bone Joint Surg Am. 2003, 85-A Suppl 2: 17-24.

    PubMed  Google Scholar 

  11. 11.

    Grande DA, Singh IJ, Pugh J: Healing of experimentally produced lesions in articular cartilage following chondrocyte transplantation. Anat Rec. 1987, 218: 142-148.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Grande DA, Pitman MI, Peterson L, Menche D, Klein M: The repair of experimentally produced defects in rabbit articular cartilage by autologous chondrocyte transplantation. J Orthop Res. 1989, 7: 208-218.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Navsaria HA, Myers SR, Leigh IM, McKay IA: Culturing skin in vitro for wound therapy. Trends Biotechnol. 1995, 13: 91-100. 10.1016/S0167-7799(00)88913-1.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Kuroyanagi Y, Kenmochi M, Ishihara S, Takeda A, Shiraishi A, Ootake N, Uchinuma E, Torikai K, Shioya N: A cultured skin substitute composed of fibroblasts and keratinocytes with a collagen matrix: preliminary results of clinical trials. Ann Plast Surg. 1993, 31: 340-9; discussion 349-51.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Lam PK, Chan ES, Liew CT, Yen RS, Lau HC, King WW: Dermal fibroblasts do not enhance the graft take rate of autologous, cultured keratinocyte suspension on full-thickness wounds in rats. Ann Plast Surg. 2001, 46: 146-149. 10.1097/00000637-200102000-00010.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Boyce ST, Greenhalgh DG, Kagan RJ, Housinger T, Sorrell JM, Childress CP, Rieman M, Warden GD: Skin anatomy and antigen expression after burn wound closure with composite grafts of cultured skin cells and biopolymers. Plast Reconstr Surg. 1993, 91: 632-641.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Carsin H, Ainaud P, Le Bever H, Rives J, Lakhel A, Stephanazzi J, Lambert F, Perrot J: Cultured epithelial autografts in extensive burn coverage of severely traumatized patients: a five year single-center experience with 30 patients. Burns. 2000, 26: 379-387. 10.1016/S0305-4179(99)00143-6.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Penn MS, Francis GS, Ellis SG, Young JB, McCarthy PM, Topol EJ: Autologous cell transplantation for the treatment of damaged myocardium. Prog Cardiovasc Dis. 2002, 45: 21-32. 10.1053/pcad.2002.123466.

    Article  PubMed  Google Scholar 

  19. 19.

    Yoo KJ, Li RK, Weisel RD, Mickle DA, Li G, Yau TM: Autologous smooth muscle cell transplantation improved heart function in dilated cardiomyopathy. Ann Thorac Surg. 2000, 70: 859-865. 10.1016/S0003-4975(00)01630-1.

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Dorfman J, Duong M, Zibaitis A, Pelletier MP, Shum-Tim D, Li C, Chiu RC: Myocardial tissue engineering with autologous myoblast implantation. J Thorac Cardiovasc Surg. 1998, 116: 744-751.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Al Attar N, Carrion C, Ghostine S, Garcin I, Vilquin JT, Hagege AA, Menasche P: Long-term (1 year) functional and histological results of autologous skeletal muscle cells transplantation in rat. Cardiovasc Res. 2003, 58: 142-148. 10.1016/S0008-6363(02)00790-3.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Tran N, Li Y, Bertrand S, Bangratz S, Carteaux JP, Stoltz JF, Villemot JP: Autologous cell transplantation and cardiac tissue engineering: potential applications in heart failure. Biorheology. 2003, 40: 411-415.

    PubMed  Google Scholar 

  23. 23.

    Gulbins H, Meiser BM, Reichenspurner H, Reichart B: Cell transplantation--a potential therapy for cardiac repair in the future?. Heart Surg Forum. 2002, 5: E28-34.

    PubMed  Google Scholar 

  24. 24.

    Peyman GA, Blinder KJ, Paris CL, Alturki W, Nelson N. C., Jr., Desai U: A technique for retinal pigment epithelium transplantation for age-related macular degeneration secondary to extensive subfoveal scarring. Ophthalmic Surg. 1991, 22: 102-108.

    CAS  PubMed  Google Scholar 

  25. 25.

    Ishida M, Lui GM, Yamani A, Sugino IK, Zarbin MA: Culture of human retinal pigment epithelial cells from peripheral scleral flap biopsies. Curr Eye Res. 1998, 17: 392-402.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Binder S, Stolba U, Krebs I, Kellner L, Jahn C, Feichtinger H, Povelka M, Frohner U, Kruger A, Hilgers RD, Krugluger W: Transplantation of autologous retinal pigment epithelium in eyes with foveal neovascularization resulting from age-related macular degeneration: a pilot study. Am J Ophthalmol. 2002, 133: 215-225. 10.1016/S0002-9394(01)01373-3.

    Article  PubMed  Google Scholar 

  27. 27.

    Semkova I, Kreppel F, Welsandt G, Luther T, Kozlowski J, Janicki H, Kochanek S, Schraermeyer U: Autologous transplantation of genetically modified iris pigment epithelial cells: a promising concept for the treatment of age-related macular degeneration and other disorders of the eye. Proc Natl Acad Sci U S A. 2002, 99: 13090-13095. 10.1073/pnas.202486199.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  28. 28.

    Baron-Van Evercooren A, Avellana-Adalid V, Lachapelle F, Liblau R: Schwann cell transplantation and myelin repair of the CNS. Mult Scler. 1997, 3: 157-161.

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Blakemore WF, Crang AJ: The use of cultured autologous Schwann cells to remyelinate areas of persistent demyelination in the central nervous system. J Neurol Sci. 1985, 70: 207-223. 10.1016/0022-510X(85)90088-7.

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Stangel M, Hartung HP: Remyelinating strategies for the treatment of multiple sclerosis. Prog Neurobiol. 2002, 68: 361-376. 10.1016/S0301-0082(02)00105-3.

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Wrathall JR, Kapoor V, Kao CC: Observation of cultured peripheral non-neuronal cells implanted into the transected spinal cord. Acta Neuropathol (Berl). 1984, 64: 203-212.

    CAS  Article  Google Scholar 

  32. 32.

    Cheng B, Chen Z: Fabricating autologous tissue to engineer artificial nerve. Microsurgery. 2002, 22: 133-137. 10.1002/micr.21740.

    Article  PubMed  Google Scholar 

  33. 33.

    Bentley G, Biant LC, Carrington RW, Akmal M, Goldberg A, Williams AM, Skinner JA, Pringle J: A prospective, randomised comparison of autologous chondrocyte implantation versus mosaicplasty for osteochondral defects in the knee. J Bone Joint Surg Br. 2003, 85: 223-230. 10.1302/0301-620X.85B2.13543.

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR: Multilineage potential of adult human mesenchymal stem cells. Science. 1999, 284: 143-147. 10.1126/science.284.5411.143.

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Takagi K, Urist MR: The role of bone marrow in bone morphogenetic protein-induced repair of femoral massive diaphyseal defects. Clin Orthop. 1982, 224-231.

    Google Scholar 

  36. 36.

    Wakitani S, Goto T, Pineda SJ, Young RG, Mansour JM, Caplan AI, Goldberg VM: Mesenchymal cell-based repair of large, full-thickness defects of articular cartilage. J Bone Joint Surg Am. 1994, 76: 579-592.

    CAS  PubMed  Google Scholar 

  37. 37.

    Im GI, Kim DY, Shin JH, Hyun CW, Cho WH: Repair of cartilage defect in the rabbit with cultured mesenchymal stem cells from bone marrow. J Bone Joint Surg Br. 2001, 83: 289-294. 10.1302/0301-620X.83B2.10495.

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Wakitani S, Imoto K, Yamamoto T, Saito M, Murata N, Yoneda M: Human autologous culture expanded bone marrow mesenchymal cell transplantation for repair of cartilage defects in osteoarthritic knees. Osteoarthritis Cartilage. 2002, 10: 199-206. 10.1053/joca.2001.0504.

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Orlic D, Kajstura J, Chimenti S, Bodine DM, Leri A, Anversa P: Transplanted adult bone marrow cells repair myocardial infarcts in mice. Ann N Y Acad Sci. 2001, 938: 221-9; discussion 229-30.

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Orlic D, Kajstura J, Chimenti S, Bodine DM, Leri A, Anversa P: Bone marrow stem cells regenerate infarcted myocardium. Pediatr Transplant. 2003, 7 Suppl 3: 86-88. 10.1034/j.1399-3046.7.s3.13.x.

    Article  PubMed  Google Scholar 

  41. 41.

    Terai S, Yamamoto N, Omori K, Sakaida I, Okita K: A new cell therapy using bone marrow cells to repair damaged liver. J Gastroenterol. 2002, 37 Suppl 14: 162-163.

    Article  PubMed  Google Scholar 

  42. 42.

    Chopp M, Zhang XH, Li Y, Wang L, Chen J, Lu D, Lu M, Rosenblum M: Spinal cord injury in rat: treatment with bone marrow stromal cell transplantation. Neuroreport. 2000, 11: 3001-3005.

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Akiyama Y, Radtke C, Honmou O, Kocsis JD: Remyelination of the spinal cord following intravenous delivery of bone marrow cells. Glia. 2002, 39: 229-236. 10.1002/glia.10102.

    PubMed Central  Article  PubMed  Google Scholar 

  44. 44.

    Sasaki M, Honmou O, Akiyama Y, Uede T, Hashi K, Kocsis JD: Transplantation of an acutely isolated bone marrow fraction repairs demyelinated adult rat spinal cord axons. Glia. 2001, 35: 26-34. 10.1002/glia.1067.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  45. 45.

    Ianus A, Holz GG, Theise ND, Hussain MA: In vivo derivation of glucose-competent pancreatic endocrine cells from bone marrow without evidence of cell fusion. J Clin Invest. 2003, 111: 843-850. 10.1172/JCI200316502.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  46. 46.

    Peretti GM, Caruso EM, Randolph MA, Zaleske DJ: Meniscal repair using engineered tissue. J Orthop Res. 2001, 19: 278-285. 10.1016/S0736-0266(00)90010-X.

    CAS  Article  PubMed  Google Scholar 

  47. 47.

    Eaglstein WH, Falanga V: Tissue engineering and the development of Apligraf a human skin equivalent. Adv Wound Care. 1998, 11: 1-8.

    CAS  PubMed  Google Scholar 

  48. 48.

    Chu CR, Coutts RD, Yoshioka M, Harwood FL, Monosov AZ, Amiel D: Articular cartilage repair using allogeneic perichondrocyte-seeded biodegradable porous polylactic acid (PLA): a tissue-engineering study. J Biomed Mater Res. 1995, 29: 1147-1154.

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Parenteau NL, Bilbo P, Nolte CJ, Mason VS, Rosenberg M: The organotypic culture of human skin keratinocytes and fibroblasts to achieve form and function. Cytotechnology. 1992, 9: 163-171.

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Aubock J, Irschick E, Romani N, Kompatscher P, Hopfl R, Herold M, Schuler G, Bauer M, Huber C, Fritsch P: Rejection, after a slightly prolonged survival time, of Langerhans cell-free allogeneic cultured epidermis used for wound coverage in humans. Transplantation. 1988, 45: 730-737.

    CAS  Article  PubMed  Google Scholar 

  51. 51.

    Sabolinski ML, Alvarez O, Auletta M, Mulder G, Parenteau NL: Cultured skin as a 'smart material' for healing wounds: experience in venous ulcers. Biomaterials. 1996, 17: 311-320. 10.1016/0142-9612(96)85569-4.

    CAS  Article  PubMed  Google Scholar 

  52. 52.

    Briscoe DM, Dharnidharka VR, Isaacs C, Downing G, Prosky S, Shaw P, Parenteau NL, Hardin-Young J: The allogeneic response to cultured human skin equivalent in the hu-PBL-SCID mouse model of skin rejection. Transplantation. 1999, 67: 1590-1599. 10.1097/00007890-199906270-00014.

    CAS  Article  PubMed  Google Scholar 

  53. 53.

    Subramanian T, Marchionini D, Potter EM, Cornfeldt ML: Striatal xenotransplantation of human retinal pigment epithelial cells attached to microcarriers in hemiparkinsonian rats ameliorates behavioral deficits without provoking a host immune response. Cell Transplant. 2002, 11: 207-214.

    PubMed  Google Scholar 

  54. 54.

    Watts RL, Raiser, CD, Stover, NP, Cornfeldt, ML, Schweikert, ML,, Allen RC, Somerville, NJ, Subramanian, T, Bakay, RAE: Stereotaxic Intrastriatal Implantation of Retinal Pigment Epithelial Cells Attached to Microcarriers in Six Advanced Parkinson Disease (PD) Patients: Two Year Follow-Up. American Academy of Neurology, 55th Annual Meeting, March 29 - April 5th, 2003. 2003, Honolulu, Hawaii

    Google Scholar 

  55. 55.

    Philips MF, Muir JK, Saatman KE, Raghupathi R, Lee VM, Trojanowski JQ, McIntosh TK: Survival and integration of transplanted postmitotic human neurons following experimental brain injury in immunocompetent rats. J Neurosurg. 1999, 90: 116-124.

    CAS  Article  PubMed  Google Scholar 

  56. 56.

    Borlongan CV, Tajima Y, Trojanowski JQ, Lee VM, Sanberg PR: Cerebral ischemia and CNS transplantation: differential effects of grafted fetal rat striatal cells and human neurons derived from a clonal cell line. Neuroreport. 1998, 9: 3703-3709.

    CAS  Article  PubMed  Google Scholar 

  57. 57.

    Kondziolka D, Wechsler L, Goldstein S, Meltzer C, Thulborn KR, Gebel J, Jannetta P, DeCesare S, Elder EM, McGrogan M, Reitman MA, Bynum L: Transplantation of cultured human neuronal cells for patients with stroke. Neurology. 2000, 55: 565-569.

    CAS  Article  PubMed  Google Scholar 

  58. 58.

    Nelson PT, Kondziolka D, Wechsler L, Goldstein S, Gebel J, DeCesare S, Elder EM, Zhang PJ, Jacobs A, McGrogan M, Lee VM, Trojanowski JQ: Clonal human (hNT) neuron grafts for stroke therapy: neuropathology in a patient 27 months after implantation. Am J Pathol. 2002, 160: 1201-1206.

    PubMed Central  Article  PubMed  Google Scholar 

  59. 59.

    Watanabe T, Kawano Y, Watanabe A, Takaue Y: Autologous and allogeneic transplantation with peripheral blood CD34+ cells: a pediatric experience. Haematologica. 1999, 84: 167-176. 10.1159/000015248.

    CAS  PubMed  Google Scholar 

  60. 60.

    Baron F, Baudoux E, Fillet G, Beguin Y: Retrospective comparison of CD34-selected allogeneic peripheral blood stem cell transplantation followed by CD8-depleted donor lymphocyte infusions with unmanipulated bone marrow transplantation. Hematology. 2002, 7: 137-143.

    Article  PubMed  Google Scholar 

  61. 61.

    Uchida N, Buck DW, He D, Reitsma MJ, Masek M, Phan TV, Tsukamoto AS, Gage FH, Weissman IL: Direct isolation of human central nervous system stem cells. Proc Natl Acad Sci U S A. 2000, 97: 14720-14725. 10.1073/pnas.97.26.14720.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  62. 62.

    Svendsen CN, Caldwell MA, Shen J, ter Borg MG, Rosser AE, Tyers P, Karmiol S, Dunnett SB: Long-term survival of human central nervous system progenitor cells transplanted into a rat model of Parkinson's disease. Exp Neurol. 1997, 148: 135-146. 10.1006/exnr.1997.6634.

    CAS  Article  PubMed  Google Scholar 

  63. 63.

    Svendsen CN, ter Borg MG, Armstrong RJ, Rosser AE, Chandran S, Ostenfeld T, Caldwell MA: A new method for the rapid and long term growth of human neural precursor cells. J Neurosci Methods. 1998, 85: 141-152. 10.1016/S0165-0270(98)00126-5.

    CAS  Article  PubMed  Google Scholar 

  64. 64.

    Svendsen CN, Clarke DJ, Rosser AE, Dunnett SB: Survival and differentiation of rat and human epidermal growth factor-responsive precursor cells following grafting into the lesioned adult central nervous system. Exp Neurol. 1996, 137: 376-388. 10.1006/exnr.1996.0039.

    CAS  Article  PubMed  Google Scholar 

  65. 65.

    Svendsen CN, Caldwell MA, Ostenfeld T: Human neural stem cells: isolation, expansion and transplantation. Brain Pathol. 1999, 9: 499-513.

    CAS  Article  PubMed  Google Scholar 

  66. 66.

    Nunes MC, Roy NS, Keyoung HM, Goodman RR, McKhann G., 2nd, Jiang L, Kang J, Nedergaard M, Goldman SA: Identification and isolation of multipotential neural progenitor cells from the subcortical white matter of the adult human brain. Nat Med. 2003, 9: 439-447. 10.1038/nm837.

    CAS  Article  PubMed  Google Scholar 

  67. 67.

    Keyoung HM, Roy NS, Benraiss A, Louissaint A., Jr., Suzuki A, Hashimoto M, Rashbaum WK, Okano H, Goldman SA: High-yield selection and extraction of two promoter-defined phenotypes of neural stem cells from the fetal human brain. Nat Biotechnol. 2001, 19: 843-850. 10.1038/nbt0901-843.

    CAS  Article  PubMed  Google Scholar 

  68. 68.

    Evans MJ, Kaufman MH: Establishment in culture of pluripotential cells from mouse embryos. Nature. 1981, 292: 154-156.

    CAS  Article  PubMed  Google Scholar 

  69. 69.

    Nagy A, Gocza E, Diaz EM, Prideaux VR, Ivanyi E, Markkula M, Rossant J: Embryonic stem cells alone are able to support fetal development in the mouse. Development. 1990, 110: 815-821.

    CAS  PubMed  Google Scholar 

  70. 70.

    Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM: Embryonic stem cell lines derived from human blastocysts. Science. 1998, 282: 1145-1147. 10.1126/science.282.5391.1145.

    CAS  Article  PubMed  Google Scholar 

  71. 71.

    Guan K, Chang H, Rolletschek A, Wobus AM: Embryonic stem cell-derived neurogenesis. Retinoic acid induction and lineage selection of neuronal cells. Cell Tissue Res. 2001, 305: 171-176. 10.1007/s004410100416.

    CAS  Article  PubMed  Google Scholar 

  72. 72.

    Kaufman DS, Hanson ET, Lewis RL, Auerbach R, Thomson JA: Hematopoietic colony-forming cells derived from human embryonic stem cells. Proc Natl Acad Sci U S A. 2001, 98: 10716-10721. 10.1073/pnas.191362598.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  73. 73.

    Kehat I, Kenyagin-Karsenti D, Snir M, Segev H, Amit M, Gepstein A, Livne E, Binah O, Itskovitz-Eldor J, Gepstein L: Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes. J Clin Invest. 2001, 108: 407-414. 10.1172/JCI200112131.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  74. 74.

    Dani C: Embryonic stem cell-derived adipogenesis. Cells Tissues Organs. 1999, 165: 173-180. 10.1159/000016697.

    CAS  Article  PubMed  Google Scholar 

  75. 75.

    Trounson A: Human embryonic stem cells: mother of all cell and tissue types. Reprod Biomed Online. 2002, 4 Suppl 1: 58-63.

    Article  PubMed  Google Scholar 

  76. 76.

    Odorico JS, Kaufman DS, Thomson JA: Multilineage differentiation from human embryonic stem cell lines. Stem Cells. 2001, 19: 193-204.

    CAS  Article  PubMed  Google Scholar 

  77. 77.

    Carpenter MK, Rosler E, Rao MS: Characterization and differentiation of human embryonic stem cells. Cloning Stem Cells. 2003, 5: 79-88. 10.1089/153623003321512193.

    CAS  Article  PubMed  Google Scholar 

  78. 78.

    Appel J. Z., 3rd, Alwayn IP, Cooper DK: Xenotransplantation: the challenge to current psychosocial attitudes. Prog Transplant. 2000, 10: 217-225.

    Article  PubMed  Google Scholar 

  79. 79.

    Platt JL: Immunobiology of xenotransplantation. Transpl Int. 2000, 13 Suppl 1: S7-10. 10.1007/s001470050265.

    CAS  Article  PubMed  Google Scholar 

  80. 80.

    Fodor WL, Williams BL, Matis LA, Madri JA, Rollins SA, Knight JW, Velander W, Squinto SP: Expression of a functional human complement inhibitor in a transgenic pig as a model for the prevention of xenogeneic hyperacute organ rejection. Proc Natl Acad Sci U S A. 1994, 91: 11153-11157.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  81. 81.

    Ramsoondar JJ, Machaty Z, Costa C, Williams BL, Fodor WL, Bondioli KR: Production of {alpha}1,3-Galactosyltransferase-Knockout Cloned Pigs Expressing Human {alpha}1,2-Fucosylosyltransferase. Biol Reprod. 2003

    Google Scholar 

  82. 82.

    Costa C, Zhao L, Burton WV, Bondioli KR, Williams BL, Hoagland TA, Ditullio PA, Ebert KM, Fodor WL: Expression of the human alpha1,2-fucosyltransferase in transgenic pigs modifies the cell surface carbohydrate phenotype and confers resistance to human serum-mediated cytolysis. Faseb J. 1999, 13: 1762-1773.

    CAS  PubMed  Google Scholar 

  83. 83.

    Costa C, Zhao L, Burton WV, Rosas C, Bondioli KR, Williams BL, Hoagland TA, Dalmasso AP, Fodor WL: Transgenic pigs designed to express human CD59 and H-transferase to avoid humoral xenograft rejection. Xenotransplantation. 2002, 9: 45-57. 10.1034/j.1399-3089.2002.0o142.x.

    Article  PubMed  Google Scholar 

  84. 84.

    Phelps CJ, Koike C, Vaught TD, Boone J, Wells KD, Chen SH, Ball S, Specht SM, Polejaeva IA, Monahan JA, Jobst PM, Sharma SB, Lamborn AE, Garst AS, Moore M, Demetris AJ, Rudert WA, Bottino R, Bertera S, Trucco M, Starzl TE, Dai Y, Ayares DL: Production of alpha 1,3-galactosyltransferase-deficient pigs. Science. 2003, 299: 411-414. 10.1126/science.1078942.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  85. 85.

    Dai Y, Vaught TD, Boone J, Chen SH, Phelps CJ, Ball S, Monahan JA, Jobst PM, McCreath KJ, Lamborn AE, Cowell-Lucero JL, Wells KD, Colman A, Polejaeva IA, Ayares DL: Targeted disruption of the alpha1,3-galactosyltransferase gene in cloned pigs. Nat Biotechnol. 2002, 20: 251-255. 10.1038/nbt0302-251.

    CAS  Article  PubMed  Google Scholar 

  86. 86.

    Lai L, Kolber-Simonds D, Park KW, Cheong HT, Greenstein JL, Im GS, Samuel M, Bonk A, Rieke A, Day BN, Murphy CN, Carter DB, Hawley RJ, Prather RS: Production of alpha-1,3-galactosyltransferase knockout pigs by nuclear transfer cloning. Science. 2002, 295: 1089-1092. 10.1126/science.1068228.

    CAS  Article  PubMed  Google Scholar 

  87. 87.

    Groth CG, Tibell A, Wennberg L, Korsgren O: Xenoislet transplantation: experimental and clinical aspects. J Mol Med. 1999, 77: 153-154. 10.1007/s001090050325.

    CAS  Article  PubMed  Google Scholar 

  88. 88.

    Tibell A, Groth CG, Moller E, Korsgren O, Andersson A, Hellerstrom C: Pig-to-human islet transplantation in eight patients. Transplant Proc. 1994, 26: 762-763.

    CAS  PubMed  Google Scholar 

  89. 89.

    Schumacher JM, Ellias SA, Palmer EP, Kott HS, Dinsmore J, Dempsey PK, Fischman AJ, Thomas C, Feldman RG, Kassissieh S, Raineri R, Manhart C, Penney D, Fink JS, Isacson O: Transplantation of embryonic porcine mesencephalic tissue in patients with PD. Neurology. 2000, 54: 1042-1050.

    CAS  Article  PubMed  Google Scholar 

  90. 90.

    Deacon T, Schumacher J, Dinsmore J, Thomas C, Palmer P, Kott S, Edge A, Penney D, Kassissieh S, Dempsey P, Isacson O: Histological evidence of fetal pig neural cell survival after transplantation into a patient with Parkinson's disease. Nat Med. 1997, 3: 350-353.

    CAS  Article  PubMed  Google Scholar 

  91. 91.

    Fink JS, Schumacher JM, Ellias SL, Palmer EP, Saint-Hilaire M, Shannon K, Penn R, Starr P, VanHorne C, Kott HS, Dempsey PK, Fischman AJ, Raineri R, Manhart C, Dinsmore J, Isacson O: Porcine xenografts in Parkinson's disease and Huntington's disease patients: preliminary results. Cell Transplant. 2000, 9: 273-278.

    CAS  PubMed  Google Scholar 

  92. 92.

    Levy MF, Crippin J, Sutton S, Netto G, McCormack J, Curiel T, Goldstein RM, Newman JT, Gonwa TA, Banchereau J, Diamond LE, Byrne G, Logan J, Klintmalm GB: Liver allotransplantation after extracorporeal hepatic support with transgenic (hCD55/hCD59) porcine livers: clinical results and lack of pig-to-human transmission of the porcine endogenous retrovirus. Transplantation. 2000, 69: 272-280. 10.1097/00007890-200001270-00013.

    CAS  Article  PubMed  Google Scholar 

  93. 93.

    Switzer WM, Michler RE, Shanmugam V, Matthews A, Hussain AI, Wright A, Sandstrom P, Chapman LE, Weber C, Safley S, Denny RR, Navarro A, Evans V, Norin AJ, Kwiatkowski P, Heneine W: Lack of cross-species transmission of porcine endogenous retrovirus infection to nonhuman primate recipients of porcine cells, tissues, or organs. Transplantation. 2001, 71: 959-965. 10.1097/00007890-200104150-00022.

    CAS  Article  PubMed  Google Scholar 

  94. 94.

    Dinsmore JH, Manhart C, Raineri R, Jacoby DB, Moore A: No evidence for infection of human cells with porcine endogenous retrovirus (PERV) after exposure to porcine fetal neuronal cells. Transplantation. 2000, 70: 1382-1389. 10.1097/00007890-200011150-00020.

    CAS  Article  PubMed  Google Scholar 

  95. 95.

    Martin U, Steinhoff G, Kiessig V, Chikobava M, Anssar M, Morschheuser T, Lapin B, Haverich A: Porcine endogenous retrovirus (PERV) was not transmitted from transplanted porcine endothelial cells to baboons in vivo. Transpl Int. 1998, 11: 247-251. 10.1007/s001470050136.

    CAS  Article  PubMed  Google Scholar 

  96. 96.

    Paradis K, Langford G, Long Z, Heneine W, Sandstrom P, Switzer WM, Chapman LE, Lockey C, Onions D, Otto E: Search for cross-species transmission of porcine endogenous retrovirus in patients treated with living pig tissue. The XEN 111 Study Group. Science. 1999, 285: 1236-1241. 10.1126/science.285.5431.1236.

    CAS  Article  PubMed  Google Scholar 

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Fodor, W.L. Tissue engineering and cell based therapies, from the bench to the clinic: The potential to replace, repair and regenerate. Reprod Biol Endocrinol 1, 102 (2003).

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