By Hal E. Broxmeyer, PhD
2009-01-01
Dr. Broxmeyer is Distinguished Professor, Chairman and Mary
Margaret Walther Professor of Microbiology/Immunology, and Professor of
Medicine at the Indiana University School of Medicine. He also serves
as the Scientific Director of the Walther Oncology Center. He is also
the President-Elect of ASH.
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.
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