Given the unique regenerative capabilities of cord blood, the easy accessibility of HLA matched donors, and relative inexpensiveness as compared to other cellular therapies; it is of great interest therapeutically to expand its use into non-conditioned recipients. Below we will provide some initial thoughts on how this may be performed.
Cord blood together with stem cell activators
One simple method of stem cell therapy would be administration of cord blood units in patients with degenerative diseases in the form of direct transfusions has described by Bhattacharya [57]. This approach, however has not demonstrated significant regenerative activity. A more promising approach may be administration of cord blood cells in combination with activators of endogenous stem cells. For example, clinically used agents such as thalidomide [87], valproic acid [88], or 5-azacytidine [89,90] all have demonstrated ability to induce proliferation of CD34+ stem cells in vitro and/or in vivo. In the majority of cases, stem cell activating compounds are administered for therapeutic benefit in absence of addition of exogenous stem cell sources. One example is current clinical trials of hCG and EPO for treatment of acute stroke [91]. The addition of exogeneous allogeneic stem cells to clinically accepted stem cell expanding agents may be a relatively easy initial clinical trial of regenerative cord blood therapy in absence of recipient conditioning. An interesting addition to administration of stem cell activators is the localized introduction of stem cell specific chemoattractant agents at the site in need of repair, followed by systemic administration of cord blood stem cells. Chemoattractant agents could include stromal derived growth factor-1 [92], other various agonists of CXCR-4 [93], or hepatocyte growth factor [94].
Cord blood plus natural chemoattractant
An alternative approach to administration of exogenous stem cell chemoattractants would be to administer stem cells at the narrow window period after tissue injury when endogenous chemoattractants are secreted by the injured tissue. For example, following myocardial infarction, as well as stroke, there is a period of time which concentration of local stem cell chemoattractants are so high that bone marrow derived progenitors are actually mobilized into systemic circulation [95]. Activators of endogenous stem cells may be administered to allow localized tissue repair, while exogenous stem cells are administered to provide support to the activated endogenous cells.
De-immunogenized cord blood graft
Clinical entry of a cord blood therapeutic in patients who are not preconditioned would require a high margin of safety to be met. Accordingly, one approach for beginning cord blood clinical trials may be administration of grafts that are depleted of T cells, B cells, and dendritic cells. In this manner, even the remote possibility of GVHD would be negated, and the there would be no B cell or dendritic cell induced antigenicity. Essentially, the percentage stem cell content of the graft would increase while the possible immunogenic components would decrease. A method of accomplishing this would be the pretreatment of cord blood units with the clinically used anti-CD52 monoclonal antibody CAMPATH. It has been previously demonstrated that this agent can be used in substantially "cleaning" grafts of T cells without affecting hematopoietic activity both in vitro [96] and in the clinic [97]. Furthermore, CAMPATH has been shown to deplete B cells [97], as well as circulating blood dendritic cells [98,99]. An ideal indication for utilization of such a treatment would be in limb ischemia in which a variety of stem cell sources have demonstrated angiogenic effects, however clinical implementation of stem cells for limb ischemia is currently limited by the difficulties of obtaining and purifying autologous stem cells.
Answers to all your Biology Questions
