The first widespread utilization of cord blood as a stem cell source was in the treatment of pediatric hematological malignancies after myeloablative conditioning. Since matching requirements for this type of transplant are not as strict as for hematopoietic stem cell sources, cord blood began gaining acceptance in adult patients lacking bone marrow donors [1-6]. Outside the area of oncology, the clinical use of cord blood has expanded into various areas that range from reconstituting a defective immune system [7], to correcting congenital hematological abnormalities [8], to inducing angiogenesis [9]. A sample of some of cord blood clinical studies addressing non-malignant disorders is presented in Table 1.
In addition to current clinical use, cord blood is currently under intense experimental investigation in preclinical models of pathophysiologies that range from myocardial ischemia, to stroke, to muscle regeneration [10-13]. It is anticipated that in the next several years that widespread clinical entry of cord blood for non-hematopoietic tissue regeneration will occur. When this happens, the main question will be how to select patients that can be myeloablated so as to allow acceptance of the cord blood graft. According to current dogma in the discipline, it is believed that myeloablation, or at minimum non-ablative immune suppression of the recipient is strictly required. In situations of hematological malignancy it is desirable to myeloablate the recipient so as to eradicate the leukemic population while creating "space" for the donor cells to engraft. However, the question is, in patients that are not suffering from a disease that is associated with an aberrant bone marrow such as hematological malignancies or immunological dysfunctions, how is it justifiable to subject them to the high levels of morbidity and mortality associated with immune suppression? For conditions such as Krabbe disease where patients rarely survive beyond the age of 2 and cord blood transplant was demonstrated to induce 100% survival in a subgroup of patients treated [14], the justification for myeloablation can be made. However for conditions such as post-stroke regeneration or induction of angiogenesis in angina patients, in which the population already suffers from major comorbidities and the potential benefit of cord blood therapy is only speculative, the ability to justify myeloablative protocols rapidly diminishes.
The purpose of this paper is to put forth the notion that the immunology of cord blood transplants for regenerative applications has to be viewed differently from the perspective and the practice of cord blood transplants for hematopoietic reconstitution. Specifically, we will provide reasons and rational for why in some situations, administration of cord blood, or stem cells derived thereof, may be possible with no, or minimal immune suppression of the recipient. Evaluation of this possibility will lead to acceleration of clinical entry and wide-spread utilization of cord blood transplants for non-hematopoietic indications.
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