Stem-Cell “Hype” in Tracheal Transplantation?

Composite tissue allotransplantation (CTA) involves the transplantation of various tissues as opposed to a single separate organ in conventional transplantation; CTA is a new therapeutic modality to reconstruct major tissue defects of the face and upper extremities (1, 2). Restoration of the blood supply and the administration of immunosuppressive drugs to prevent rejection are essential in CTA. The trachea poses a special challenge in CTA because of difficulties in restoring the blood supply; therefore, the trachea has been transplanted repeatedly as an avascular graft. Unfortunately, allotransplantation of an avascular trachea in an immunosuppressed recipient will inevitably lead to necrosis of the transplant. Orthotopic revascularization of the trachea, in which the trachea is wrapped with well-vascularized tissue of the recipient, is not possible because of the continuous movement of the transplant during breathing, swallowing, and coughing and the exposure of ischemic mucosal lining to the aggressive environment of the airway lumen (3). Revascularization of the trachea can only take place in a heterotopic position, where an immobile trachea is surrounded by well-revascularised tissue of the immunosuppressed recipient (4, 5). As with all other CTAs, the trachea can be transplanted when the blood supply is restored in an immunosuppressed host (5). Vascularized tracheal allotransplantation was recently presented with long-term computed tomographic documentation of tracheal allograft viability (5). An article published in Lancet in 2008, reporting on a tissue-engineered tracheal transplant, challenged our current knowledge of composite tissue transplantation (6). Recipient stem cells were used; therefore, immunosuppressive drugs could be avoided, and restoration of the blood supply was not necessary. The sequence of steps followed in creating and using the transplant is summarized in the Figure 1.FIGURE 1.: (A) The native tracheal blood vessels are too small to allow for revascularization by microvascular anastomosis between the donor and recipient blood vessels (1). Transplantation of an avascular allotransplant into an airway defect of an immunosuppressed host will lead to necrosis (2). Orthotopic revascularization attempts, in which the allotransplant is wrapped with vascularized recipient tissue, will fail (3). (B) Because of the various enzymatic treatments, the donor respiratory epithelial cells and chondrocytes are washed away (1). Repopulation of the cartilage rings occurs by bone marrow stem cells, and the lining is reestablished by cultured airway epithelial cells (2). The tissue-engineered construct is placed into an airway defect with a reportedly successful outcome (3).An enzymatically decellularized donor trachea was suspended with recipient cells, and the recipient bone marrow stem cells reportedly colonized the cartilaginous rings. Cultured recipient airway epithelium was used to repopulate the epithelial tracheal lining. However, it is difficult to understand the cellular repopulation in which stem cells find their way through a cartilaginous matrix to the empty lacunae of the enzymatically removed chondrocytes, and epithelial cells adhere to an avascular, enzymatically treated base. It seemed that this tissue construct was fully repopulated by recipient cells, so that it could be transplanted without immunosuppressive medication. It is rather miraculous that this tissue-engineered construct could be transplanted without restoration of the blood supply. This potential for regeneration in the absence of any blood supply is new and has never been observed in medicine before. Unfortunately, clear evidence for the repopulation process and for the survival of the tissue-engineered trachea was lacking (7). To evaluate the degree of cellular repopulation, the authors would need to provide histologic evidence of the tracheal transplant after the enzymatic treatment and the repopulation process. Posttransplantation coronal and axial computed tomographic scans through the reconstructed airway could be helpful to follow-up the healing process of the tissue-engineered transplant. Two years have elapsed since the initial publication, and no additional evidence has been provided so far. Recently, an article published in BMJ reported on a new case days after transplantation of a tissue-engineered transplant in a child with a tracheal defect (8). An editorial in Transplantation was published in March 2010 reporting on the same case initially published in the Lancet without new information and without new evidence of how the transplant survived within the main bronchial defect (9). I would like to urge Macchiarini and coworkers to provide more evidence. The medical community needs to be informed objectively on this new development. If this construct works, it will revolutionize tissue engineering and CTA. The engineering of other hollow tissues and organs such as the esophagus, bowel, and larynx will quickly follow, as the authors suggested (10). However, based on our current knowledge of wound healing and CTA, there is also a possibility that the avascular tissue-engineered transplant underwent necrosis, and the bronchial defect healed by secondary intention and wound contraction induced by the surrounding vascular bed. Data on wound healing of the tissue-engineered transplant are urgently warranted to distinguish between survival and necrosis of the tissue-engineered construct within the airway defect.