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Umbilical Cord Blood and Type 1 DiabetesA road ahead or dead
end?
It is our anticipation and hope that stemcells will cure type 1
diabetes somedaybecause of their limitless capacity to
differentiate as needed into the vital tissueor organ.
In theory, pluripotent cells have thecapacity to reprogram a
hostile immuneresponse to tolerate pancreatic -cells andto
regenerate pancreatic -cell mass. Thesetwo factors are the
necessary ingredients forreversing type1 diabetes.However,in
prac-tice there are many unanswered scientificquestions that need
clarification before we
claim success.In this issue ofDiabetes Care, Haller et
al. (1) report their interim results aboutautologous umbilical
cord blood infusioninto young children with type 1
diabetes.Children aged 1 year who developedtype 1 diabetes and had
banked umbilicalcord blood at an approved center wererecruited into
this study at the Universityof Florida. Cord blood infusion was
per-formed after the diagnosis of type 1 dia-betes at a mean time
of 4.1 months (range2.57.1) and into children with a mean
age of 5.5 years (3.17.3). The childrenwere brought back for
clinical, metabolic,and immunologic evaluation at 3, 6, 9,and 12
months after umbilical cord bloodtransfusion. Ethics considerations
pre-vented infusion of umbilical cord bloodinto an age-matched
nondiabetic controlgroup, so an age-matched group of type 1diabetic
subjects was used for compari-son. This constraint, although
subopti-mal, will be necessary in future stem celltype 1 diabetes
trials but should not sig-nificantlycompromise our ability to
inter-pret the study outcomes.
The results of the present study areuniformly negative;
umbilical cord bloodinfusion failed to improve C-peptide, in-sulin
utilization, and A1C and did not in-crease regulatory T-cell (Treg)
levels at 12months. Assuming that the 24-month re-sults will also
fail to demonstrate efficacyin curing or ameliorating type 1
diabetes,how do we navigate the clinical complex-ities of stem cell
trials for type 1 diabetes?Not only are there several potential
cellsources that might be used for type 1 di-abetes (e.g.,
mesenchymal stem cells, he-
matopoetic stem cells, adipose-derivedstem cells, and umbilical
cord blood), butwe must also identify the appropriate con-ditions
for expanding these cells, selectingtheappropriate subpopulationsof
cells,andadministering the proper cell dose.
The rationale for testing umbilicalcord blood in young children
with type 1diabetes is primarily related to safety. In-deed, the
results to date suggest that um-bilical cord blood infusion is
without sideeffects and can be given safely to childrenwith type 1
diabetes. The matter of effi-
cacy is more problematic. The presentstudy gives us a strong
negative signal thatsimple umbilical cord blood infusionmight not
provide a road forward towardcuring type 1 diabetes. Two
importantconsiderations need to be resolved beforewe can reach this
final conclusion: 1) thedose of umbilical cord blood in this
studymight be suboptimal to reverse type 1 di-abetes and 2) a
transient rise in Tregsbearing CD4CD25 surface markerswas observed
at 6 months after umbilicalcord blood but not at 12 months.
These
two issues are interrelated because a sub-optimal dose of
umbilical cord bloodmight provide neither the critical mass ofTregs
to control autoimmunity nor therequisite number of stem cells to
increasepancreatic -cell mass. Improvements incryopreservation
techniques and expan-sion of umbilical cord blood stem cellsprior
to therapeutic infusion might over-come these problems in the
future.
Although at present we have no road-map for the use of stem
cells to reversetype 1 diabetes in children, two promis-ing
research discoveries might provide uswith clues for future clinical
trials. Re-cently, Zhao et al. (2,3) used human um-bilical cord
blood stem cells to reversetype 1 diabetes in nonobese
diabetic(NOD) mice. These investigators devel-oped coculture
techniques by mixingnondiabetic human umbilical cord bloodstem
cells with NOD mouse spleen cellsto generate an unconventional
subset ofTregs bearing CD4CD62L but notCD25on the cell surface.
These uncon-ventional Tregs, when injected into dia-betic NOD mice,
reversed type 1 diabetes
75% of the time and stimulated pancre-atic -cell regeneration.
ConventionalTregs bearing CD4CD25FoxP3 (noteFoxP3 is a
transcription factor that de-marcates functional Tregs) did not
pos-sess these regenerative properties. Theseunconventional
CD4CD62L cellscould only be derived using purified hu-man cord
blood stem cells from healthydonors but not from type 1 diabetes
do-nors (Y. Zhao, personal communication).
Apparently, healthy umbilical cord bloodpossesses a critical
stem cell population
capable of reeducating and transformingdiabetic regulatory cells
into regenerativeCD4CD62L cells capable of reversingtype 1
diabetes. Conversely, umbilicalcord blood obtained from
individualswho later developed type 1 diabetes doesnot contain this
critical stem cell popula-tion and therefore might not be a
usefulsource of regenerative cells. Althoughthere is danger in
extrapolating insightsgained from studies in NOD mice to chil-dren
with type 1 diabetes, this neverthe-less might explain why the
present study
has failed so far. Maybe conventionalTregs bearing CD4CD25 on
their cellsurface are the wrong regenerative cellpopulation? In
addition, Bluestone andcolleagues (4) demonstrated that
conven-tional polyclonal CD4CD25 Tregswere minimally effective at
reversing type1 diabetes in NOD mice, but purified
an-tigen-specific CD4CD25 T-cells re-versed type 1 diabetes in 60%
of NODmice. Here also, if we permit extrapola-tion from mouse to
human, we encountera potential problem with umbilical cordblood
infusion in type 1 diabetic childrenbecause umbilical cord blood
cells con-tain primarily polyclonal Tregs. Futurestem cell trials
for children with type 1diabetes will inevitably lean on
discover-ies made in rodent models of the disease,inherent
limitations notwithstanding. Itbehooves us to use our translational
sci-ence wisely to sort out the limitless vari-ables that are
likely to complicate humanstem cell trials for type 1 diabetes.
In summary, the present study usingumbilical cord blood infusion
in childrenwith newly diagnosed type 1 diabetes has
E d i t o r i a l s
E D I T O R I A L ( S E E H A L L E R E T A L . , P . 2 0 4 1
)
2138 DIABETES CARE, VOLUME 32, NUMBER 11, NOVEMBER 2009
care.diabetesjournals.org
