An international conference on cord blood (CB) cells, organized by Eliane Gluckman, MD, was held October 16-19, 2008, in Mandelieu, France, celebrating the 20th anniversary of the first CB transplant and 10th anniversary of NETCORD. The first CB transplant was performed in Paris on October 6, 1988, under the pioneering direction of Dr. Gluckman, with advice from me. Donor CB was tested, frozen, and stored in my laboratory as an ongoing proof of principle CB bank. Since then, more than 400,000 CB units have been collected and stored in more than 100 CB banks, and more than 14,000 cord blood transplants have been performed for a wide range of disorders, mainly with unrelated cells.
A highlight of the meeting was the opening ceremony in which many of the pioneers in the field offered brief reminiscences. Speakers included Mr. Farrow, recipient of the first CB transplant, and Drs. Gluckman, Arleen Auerbach, Joanne Kurtzberg, Pablo Rubinstein, Marcela Contreras, Peter Wernet, Paolo Rebulla, Jon Van Rood, and John Wagner. I also spoke during the meeting. This elicited fond memories of the international collaborative efforts that culminated in the first and subsequent CB transplants. The meeting covered CB hematopoietic stem cells (HSCs) and other stem cells, banking, and clinical transplantation. A webcast from this conference will soon be available via www.eurocord-ed.org, www.esh.org, and www.eurocord.org, and summaries of selected presentations are provided below.
Dr. Vanderson Rocha noted that 2,000 to 3,000 CB transplants per year have been performed in the last four years, and since 2005 more adults than children have received transplants. The driving forces for these trends are comparable outcomes between unrelated marrow and CB in adults, use of reduced-intensity conditioning (RIC), and double CB transplants. Improved outcome for adult transplants with single CB reflect better donor choice, better definition of indications, modifications in conditioning regimens, and better graft-versus-host disease (GVHD) prophylaxis. Dr. Wagner shared encouraging results with use of two CBs. Dr. Juliet Barker presented updates on RIC/non-myeloablative transplantation and discussed approaches to ensure engraftment, differences in efficacy in specific disease entities, and guidelines for patient selection. Dr. Kurtzberg reported CB as a source of cells for treatment of children with liposomal storage diseases, with correction of damage to non-hematopoietic tissue. Dr. Kurtzberg noted that post-thaw hematopoietic progenitor cell (CFU) analysis correlates best with engraftment and survival, and should be considered a measure of banked CB potency.
New biological insights were presented by Dr. Irwin Bernstein, who noted that Notch signaling in HSC-enriched populations is mediated primarily by Notch 2. Induction of signaling in CB CD34+ cells with the Notch ligand Delta 1 expands CD34+ cell number and provides accelerated engraftment in HSC transplantation. Dr. Elizabeth Shpall described ex-vivo expansion of HSCs by co-culture of CB mononuclear cells with bone marrow-derived mesenchymal stem/stromal cells. Using this approach, the first six patients recovered neutrophils and platelets in 14.5 and 30 days, respectively. She also presented preclinical studies in NOD/SCID and NOG mice in which pretreatment of human CB progenitors with fucosyltransferase-VI reversed the homing defect of these cells.
New developments in stem cell biology were reported by Dr. Mariusz Ratajczak, who discussed very small embryonic/epiblast-like stem cells (VSELs). These cells, which are smaller than erythrocytes, are CD133+lin-CD45- and express high levels of aldehyde dehydrogenase, SSEA-4, and Oct4. Freshly isolated VSELs only show hematopoietic activity after co-culture on OP-9 stromal cells. Routine CB processing strategies lead to 60 percent loss of VSELs. Dr. Mervin Yoder noted that human circulating endothelial progenitor cells (EPCs) continue to be difficult to isolate and characterize. Populations of circulating progenitors previously reported to contain EPCs are devoid of endothelial differentiation and in vivo vessel formation, and enriched in HSCs. Newer multiparameter fluorescence activated cell sorting (FACS) approaches may define the relatively abundant progenitor cells (previously called EPCs) and extremely rare, true EPCs. Dr. Paul Simmons described development of new biomarkers such as angiotensin-converting enzyme as a characteristic of human CB SCID repopulating cells (HSC). A subpopulation of CB CD34+ cells expressed uPARAP/Endo180/ CD280, a cell adhesion molecule with homology to selectins. A proportion of CB CD34+ cells expressed endoglycan, but not podocalyxin, members of the CD34 family.
Dr. Frederik Falkenburg reported that a major difference between adult blood and CB is that adult blood contains both memory and naïve T cells, while CB contains only naïve cells, presumably because CB has not been exposed to allo-antigens (except perhaps maternal antigens). After mismatched transplant, the memory compartment contributes to GVHD. Dr. Dominique Charron described immune reconstitution as a key prognostic factor in predicting outcome of HSC transplantation. After CB transplantation, reconstitution of the T-cell repertoire, although slightly delayed, is fully complete and diverse, while it remains incomplete and skewed after adult stem cell transplantation. This may explain the lower incidence of GVHD after CB transplantation. In anticipation of the decline in stem cells with age, Dr. Charron proposed collection and cryopreservation of CB leukocytes as a bioresource for restoration of immunity and development of adoptive immunotherapies, particularly in aging populations.
Dr. Tsvee Lapidot discussed physiological interactions governing bone remodeling, HSCs, and evolving niches via neurotransmitter signaling, creating a regulatory "brain-bone-blood" triad to the HSC niche. I presented mechanistic insights into engraftment through an SDF-1/CXCL12-CXCR4 and CD26/dipeptidyl peptidase IV axis, in which SDF-1/CXCL12 control of migration, homing, and survival of HSCs was negatively modulated by CD26. Moreover, CD26 negatively modulates actions of selected colony-stimulating factors (CSFs). Inhibition of CD26 enhances the activities of these CSFs — effects that may allow enhanced engraftment and recovery of hematopoiesis after cytotoxic conditioning and/or transplantation. I also discussed a role for SIRT1, a deacytalase, in regulation of maintenance of stemness and in differentiation of HSCs.
This meeting, along with the 6th International Cord Blood Transplantation conference in Los Angeles, CA, in June, which also celebrated the 20th anniversary of the first CB transplant, was a welcome celebration of the past, a confirmation of how far we have come in the 20 years since the first transplant, and how much more we have yet to learn.
