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Per-Ola Carlsson,1,2 Erik Schwarcz,3 Olle Korsgren,4 and Katarina Le Blanc5

Preserved b-Cell Function in
Type 1 Diabetes by
Mesenchymal Stromal Cells
Diabetes 2015;64:587–592 | DOI: 10.2337/db14-0656

The retention of endogenous insulin secretion in type 1
diabetes is an attractive clinical goal, which opens
possibilities for long-term restoration of glucose me-
tabolism. Mesenchymal stromal cells (MSCs) constitute,
based on animal studies, a promising interventional
strategy for the disease. This prospective clinical study
describes the translation of this cellular intervention
strategy to patients with recent-onset type 1 diabetes.
Twenty adult patients with newly diagnosed type 1
diabetes were enrolled and randomized to MSC treat-
ment or to the control group. Residual b-cell function
was analyzed as C-peptide concentrations in blood in
response to a mixed-meal tolerance test (MMTT) at
1-year follow-up. In contrast to the patients in the con-
trol arm, who showed loss in both C-peptide peak val-
ues and C-peptide when calculated as area under the
curve during the 1st year, these responses were pre-
served or even increased in the MSC-treated patients.
Importantly, no side effects of MSC treatment were ob-
served. We conclude that autologous MSC treatment in
new-onset type 1 diabetes constitutes a safe and prom-
ising strategy to intervene in disease progression and
preserve b-cell function.

Despite intensive research, tested treatments have this far at
best only temporarily arrested the progressive loss of b-cells
in type 1 diabetes (1). Retention of endogenous insulin se-
cretion is an attractive goal, since it causes better glycemic
control (2) and decreases the risk of microvascular complica-
tions and severe hypo- or hyperglycemia episodes (3,4).

Mesenchymal stromal cells (MSCs) are rare non-
hematopoetic cells in the bone marrow that produce
matrix proteins and contribute to tissue regeneration
and repair (5). MSCs also have unique immunomodula-
tory capacities (6). They can suppress T-cell proliferation
in response to nominal antigens or alloantigens (7) and
upregulate the number of regulatory T cells (8,9). MSC-
mediated immunosuppression is also associated with
a reduction in inflammatory cytokine production (10).
Several factors have been implied to mediate immuno-
modulation, including transforming growth factor-b,
hepatocyte growth factor, prostaglandin-E2, interleukin-
10, indoleamine-2,3-dioxygenase (11), nitric oxide (12),
heme-oxygenase-1 (13), and matrix metalloproteinases
2 and 9 (14).

MSCs can be expanded ex vivo and have in a number
of studies in animal models of type 1 diabetes been
forwarded as an attractive therapy to ameliorate or
reverse manifest diabetes (15–17). Besides having sys-
temic immunomodulatory properties, the MSCs have
been observed to specifically home to the damaged islets
and to local pancreatic lymph nodes. MSCs show distinct
efficacy in graft-versus-host disease (GvHD) patients
(18,19) with no, or only minor, side effects. Importantly,
no increased risk of tumor development in patients
is known, and no ectopic tissue formation has been
observed (20,21).

The current study aimed to evaluate the safety and
efficacy of autologous MSCs in treatment of patients
recently diagnosed with type 1 diabetes.

1Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
2Department of Medical Sciences, Uppsala University, Uppsala, Sweden
3Department of Internal Medicine, Örebro University Hospital, Örebro, Sweden
4Department of Immunology, Genetics and Pathology, Uppsala University, Up-
psala, Sweden
5Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden

Corresponding author: Per-Ola Carlsson, per-ola.carlsson@mcb.uu.se.

Received 24 April 2014 and accepted 2 September 2014.

Clinical trial reg. no.

N

CT01068951, clinicaltrials.gov.

This article contains Supplementary Data online at http://diabetes
.diabetesjournals.org/lookup/suppl/doi:10.2337/db14-0656/-/DC1.

O.K. and K.L.B. share last authorship and contributed equally to this study.

© 2015 by the American Diabetes Association. Readers may use this article as
long as the work is properly cited, the use is educational and not for profit, and
the work is not altered.

Diabetes Volume 64, February 2015 587

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mailto:per-ola.carlsson@mcb.uu.se

http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db14-0656/-/DC1

http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db14-0656/-/DC1

RESEARCH DESIGN AND METHODS

Patient Selection
Patients newly diagnosed with type 1 diabetes at Uppsala
University Hospital or neighboring admitting hospitals
were enrolled according to the preset criteria: 18–40 years
of age with type 1 diabetes diagnosed ,3 weeks before
enrollment and with a stimulated C-peptide level .0.1
nmol/L. None of the patients were allowed to be preg-
nant; have BMI .30; have tested positive for HIV, viral
hepatitis B or C, or Treponema pallidum; be immune sup-
pressed; or have known or previous malignancy. All par-
ticipants were given oral and written information about
the study and signed a written consent prior to inclusion
to the study. The study was approved by the Uppsala
ethics board, and the reported investigations were per-
formed in accordance with the principles of the Declara-
tion of Helsinki as revised in 2000.

Study Design
The study was an open, single-center, randomized pilot
study at Uppsala University Hospital to evaluate the
safety using autologous MSCs in treatment of recently
diagnosed type 1 diabetes. Patients meeting the inclusion
criteria were randomized in equal numbers (10 in each
group for either MSC treatment or only insulin treat-
ment). As secondary end points, treatment efficacy was
evaluated and assessments included maintained fasting
C-peptide and evoked C-peptide response to a mixed-meal
tolerance test (MMTT), blood glucose control by HbA1c,
changes in insulin doses per kilogram, and changes in
levels of autoantibodies to b-cells (GAD65 and IA2 anti-
bodies). Study end points were evaluated at 10 weeks
after diagnosis and at the 1-year follow-up.

Randomization and Masking
Randomization without any blocking restriction was
performed by the selection of 1 of 20 identical envelopes
containing a unique identification number and group
assignment by third party member. No masking was
performed. All patients received intensive insulin therapy
(i.e., four or more injections per day) with insulin aspart
and insulin detemir on the basis of patient-measured blood
glucose levels, as well as by continuous glucose monitoring
performed on two occasions during the year. Target levels
of plasma glucose were between 5 and 8 mmol/L, and
HbA1c had a target level of ,7.0% (53 mmol/mol). The
database was maintained at Uppsala University Hospital,
and measurements of C-peptide, HbA1c, GAD65, and IA2
antibodies were performed at Uppsala University Hospital
central laboratory.

MSC Treatment
Within 3 weeks of randomization, bone marrow was
aspirated from the iliac crest of the participants in the
MSC group. Clinical-grade MSCs were then generated
under good manufacturing practice conditions as accredited
by the Swedish National Board of Health and Welfare in
growth media supplemented with lysed human platelets

(final concentration 108/mL) (19). MSCs expressed
(.95%) CD73, CD90, CD105, and HLA-ABC and were
negative (,5%) for CD14, CD31, CD34, CD45, and HLA-
DR (Supplementary Fig. 1). All cells were harvested in pas-
sage 1–2 and cryopreserved before infusion. MSC release
criteria for clinical use included the following: spindle
shape morphology, absence of contamination by patho-
gens, and viability .95%. Three to four weeks after bone
marrow harvest, 2.1–3.6 3 106 autologous cells/kg (me-
dian 2.75 3 106 cells/kg) were given as one single intrave-
nous 20-min infusion without premedication.

Safety Tests
At each outpatient visit, patients in both study groups
underwent history taking to monitor for adverse events.
Specific emphasis was put on increased tendency for
infections, development of malignancy or other disease,
as well as hypo- or hyperglycemic events. During hospi-
talization, additional physical examinations and blood
analyses were performed.

Efficacy Tests
Residual b-cell function was analyzed as C-peptide con-
centrations in blood in response to an MMTT (6 mL/kg,
maximal dose of 360 mL; Resource Protein; Novartis) at
an early time point after diagnosis (10 weeks) and at the
1-year follow-up. No concomitant insulin was given at
time of testing. In order to avoid potential influence
also of their insulin detemir, this was avoided the night
before testing in all patients. Instead, the patients were
admitted to the diabetes ward and received a combined
intravenous glucose rapid-acting insulin infusion, keeping
plasma glucose levels between 3.9 and 6.3 mmol/L until
the performance of MMTT in the morning. Plasma sam-
ples for C-peptide measurements were obtained at 0, 15,
30, 60, 90, and 120 min after meal intake and analyzed
with the use of a Roche Modular E and cobas e 601 at
Uppsala University Hospital. In addition to the preset
criteria of analysis of peak C-peptide value, the repeated
measurements allowed calculations of area under the
curve (AUC). Also, daily insulin doses per kilogram and
HbA1c levels were recorded.

Immunological Monitoring
GAD65 and IA2 antibodies were analyzed at diagnosis, 10
weeks after diagnosis, and at the 1-year follow-up.

Statistics
An unpaired, two-tailed Student t test was used to com-
pare differences between two groups of parametric data,
whereas Wilcoxon rank sum test was used for nonpara-
metric data. All values are given as means 6 SEM. P values
,0.05 were considered statistically significant.

RESULTS

Characteristics of the Patients
Twenty-six patients newly diagnosed with type 1 diabetes
between April 2010 and May 2012 provided interest for
the study and fulfilled screening criteria (Supplementary

588 Mesenchymal Stromal Cells to Treat Type 1 Diabetes Diabetes Volume 64, February 2015

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http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db14-0656/-/DC1

Fig. 2). Four of these declined to participate before ran-
domization, whereas the remaining 22 were randomized.
Two of these declined after randomization due to assign-
ment to the control group, and these two participants
were therefore substituted in the randomization. Two
of the total 20 patients in the study (one in the MSC
group and one in the control group) withdrew during the
1-year study period. The patients who withdrew stated
lack of time (the subject in the MSC group moved) and
motivation. Most patients interested in participating in
the study were males. The participants did not differ in
age, weight, BMI, or clinical or laboratory parameters
(Table 1).

Adverse Events
All patients (n = 10) randomized to autologous treatment
with MSCs tolerated the procedure well. No side effects
were observed. During the 1st year, no tumors or chronic
infections have been diagnosed in any of the study
patients. Neither did any of the patients report infections
requiring treatment with antibiotics. Several of the
patients have had episodes of viral upper respiratory tract
infections, but with similar frequency in both study
groups. One of the patients in the control group has
been diagnosed with microscopic colitis and Horton
headache. None of the study patients have had any epi-
sodes of either hyperglycemic ketoacidosis or assisted
hypoglycemia.

Efficacy Evaluation
In order to avoid effects of glucose toxicity and b-cell
exhaustion, the first MMTT was performed 10 weeks
after the start of insulin treatment. At this time point,
there were no differences in HbA1c, insulin doses per
kilogram, fasting C-peptide, or MMTT-evoked C-peptide
response (Table 2). Similarly, at the 1-year follow-up, the
study groups did not differ in these parameters. Changes
during the 1st year in C-peptide response to an MMTT
were evaluated as primary efficacy end point. In response
to the MMTT, patients in the control arm had a mean
decrease in both C-peptide peak values and C-peptide
when calculated as AUC during the 1st year. In contrast,
these responses were preserved in MSC-treated patients
(Fig. 1). For individual subjects in the control group,
8 out of 9 patients decreased in peak C-peptide, and
7 out of 9 decreased in AUC response to the MMTT
during this 1st year (Fig. 2). Notably, only 3 of the
9 MSC-treated patients decreased their peak C-peptide
or AUC response to the MMTT during the same period.

There were no changes in frequency of GAD65 or IA2
antibodies between control and MSC-treated patients.
During the year, two patients in the control arm
and one in the MSC group lost GAD65 antibodies. No
seroconversion for presence of IA2 antibodies occurred
at all.

DISCUSSION

This is the first study to report on the possibility to
intervene in the course of type 1 diabetes by systemic
MSC treatment. During the 1st year, we observed pre-
served or even increased C-peptide response to an MMTT
in MSC-treated patients.

Similar to what has been reported in interventional
studies with MSCs for other diagnoses, e.g., GvHD (19),
Crohn disease, and multiple sclerosis, we observed no
adverse events.

Composite type 1 diabetes TrialNet data indicate
a mean 15% decrease in the AUC response to an MMTT

Table 1—Characteristics of the patients at diagnosis

Characteristic
Control
(n = 9)

MSC
treated (n = 9)

Sex (male/female) 5/4 8/1

Age (years) 27 6 2 24 6 2

Body weight (kg) 68 6 4 78 6 3

BMI (kg/m2) 22.5 6 0.9 23.3 6 1.1

GAD65 antibodies (no. of all) 8/9 6/9

IA2 antibodies (no. of all) 4/9 6/9

Both GAD65 and IA2
antibodies (no. of all) 4/9 3/9

Diabetes-associated HLA alleles
DR4 (no. of all) 8/9 7/9
DR3 (no. of all) 0/9 0/9
Neither DR3 nor DR4 (no. of all) 1/9 2/9
DQ8 (no. of all) 9/9 7/9
DQ2 (no. of all) 4/9 4/9
DQ2/8 (no. of all) 3/9 2/9
Neither DQ2 nor DQ8 (no. of all) 0/9 0/9
DR4-DQ8 (no. of all) 8/9 7/9

Diabetic ketoacidosis (no. of all) 1/9 1/9

Polyuria and weight loss (no. of all) 8/9 9/9

Plus-minus values are means 6 SEM. There were no statistically
significant differences between the two groups. Concentrations of
GAD65 and IA2 antibodies were determined by ELISA technique,
where values of GAD IgG $5 units/mL and IA2 IgG $8 kU/L in-
dicated their presence. HLA class II alleles were measured with
PCR amplification and sequence-specific hybridization.

Table 2—Comparison in functional parameters between the two groups at 10 weeks after diagnosis and at 1-year follow-up

Functional parameter 10 weeks control 10 weeks MSC-treated 1-year control 1-year MSC-treated

HbA1c [% (mmol/mol)] 6.9 6 0.4 (52 6 4) 6.5 6 0.4 (48 6 4) 6.6 6 0.2 (49 6 2) 6.3 6 0.2 (46 6 2)

Insulin dose (IU/kg/day) 0.39 6 0.13 0.43 6 0.05 0.37 6 0.07 0.39 6 0.05

Fasting C-peptide (nmol/L) 0.28 6 0.02 0.29 6 0.05 0.29 6 0.04 0.32 6 0.05

All values are given as means 6 SEM for nine patients in each group. There were no statistically significant differences between the
groups.

diabetes.diabetesjournals.org Carlsson and Associates 589

http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db14-0656/-/DC1

during the 1st year in 21–46-year-old patients, and 24%
in 15–21-year-old patients (22). In our study, a mean 13%
decrease in the AUC response to an MMTT was observed
during the 1st year in patients randomized to the control
group. In contrast, most patients randomized to MSC

treatment increased their capacity for C-peptide response
to the MMTT during the study period, with increased
delta values for both peak C-peptide response and AUC
C-peptide response to the MMTT, when compared with
the control group. There were more females in the control

Figure 1—Changes in C-peptide response to an MMTT between 10 weeks after diagnosis and the 1-year follow-up for control (closed bars)
and MSC-treated type 1 diabetic patients (open bars). Absolute (A) and percent (B) changes in peak C-peptide concentrations between the
loads. Absolute (C) and percent (D) changes in the AUC response of C-peptide concentrations between the loads. All values are expressed
as means 6 SEM for nine individuals in each group. *P < 0.05 when compared with control group. Comparisons were made using Student unpaired t test.

Figure 2—C-peptide response to an MMTT at 10 weeks after diagnosis and at the 1-year follow-up for control (closed circles) and MSC-
treated type 1 diabetic patients (open circles). Peak C-peptide concentrations for all individuals in control (A) and MSC-treated group (B).
AUC response of C-peptide concentrations for the same individuals in control (C) and MSC-treated group (D).

590 Mesenchymal Stromal Cells to Treat Type 1 Diabetes Diabetes Volume 64, February 2015

group, which partially reflected the open design of study,
where two male patients randomized to control group
declined after assignment and subsequently were sub-
stituted by chance by two female patients. However,
no influence of sex on loss of C-peptide has been
reported in larger studies (22,23). Moreover, although
the male predominance in the MSC group caused a ten-
dency for these patients to weigh more, there were no
differences in BMI or insulin doses per kilogram between
the groups.

MSCs cannot only be harvested from bone marrow, as
in this study, but also from several other organs.
Moreover, culture and expansion protocols vary, as well
as the use of allogeneic or autologous cells. All these
factors may affect the cell characteristics. We chose
autologous MSC therapy to avoid any potential risk of
HLA immunization or transfer of donor-derived infec-
tions or other diseases. In our previous studies of GvHD
after hematopoietic stem cell transplantation, the 1-year
survival rate of patients was substantially higher in
patients receiving MSCs harvested in early passages
(passage 1–2) compared with later passages (passage
3–4) (20). Short-term expanded MSCs, as in the autolo-
gous setting, also elicit less innate immune attack when
infused systemically, which supports their survival and
function in vivo (24). There are reports of diabetes-
induced changes in MSCs, including their regenerative
potential, but these seem to mainly reflect effects of
long-term hyperglycemia by, e.g., advanced glycation end
products (25). In this study, we observed no defects in the
expansion potential of MSCs after autologous harvest in
subjects with recent-onset type 1 diabetes.

Results presented show that autologous MSC treat-
ment of new-onset type 1 diabetes may be a safe and
feasible strategy to intervene in the disease process and
preserve b-cell function. These encouraging results call
for larger, randomized, and double-blinded studies, with
a longer duration of follow-up, to validate the findings
obtained.

Acknowledgments. The authors thank participants, research techni-
cians, and nurses involved in the study.
Funding. This study was supported by academic grants from the Swedish
Research Council (K2013-55X-15043 and K2011-65X-12219-15-6), AFA In-
surance, EXODIAB, the Swedish Diabetes Association, the Swedish Juvenile
Diabetes Foundation, the Novo Nordisk Foundation, and Diabetes Wellness
Sverige.
Duality of Interest. No potential conflicts of interest relevant to this article
were reported.
Author Contributions. P.-O.C. conceived, designed, and conducted
the study; participated in the analysis and interpretation of the data; and
drafted the manuscript. E.S. conducted the study and critically revised the
manuscript for intellectual content. O.K. conceived and designed the study,
participated in the analysis and interpretation of the data, and critically re-
vised the manuscript for intellectual content. K.L.B. conceived, designed, and
conducted the study; participated in the analysis and interpretation of the
data; and critically revised the manuscript for intellectual content. All authors

approved the final version of the manuscript. P-O.C. is the guarantor of this
work and, as such, had full access to all the data in the study and takes
responsibility for the integrity of the data and the accuracy of the data
analysis.

References
1. von Herrath M, Peakman M, Roep B. Progress in immune-based therapies
for type 1 diabetes. Clin Exp Immunol 2013;172:186–202
2. Bonfanti R, Bazzigaluppi E, Calori G, et al. Parameters associated
with residual insulin secretion during the first year of disease in children
and adolescents with type 1 diabetes mellitus. Diabet Med 1998;15:844–
850
3. Steffes MW, Sibley S, Jackson M, Thomas W. Beta-cell function and the
development of diabetes-related complications in the diabetes control and
complications trial. Diabetes Care 2003;26:832–836
4. Shapiro AM, Ricordi C, Hering BJ, et al. International trial of the Edmonton
protocol for islet transplantation. N Engl J Med 2006;355:1318–1330
5. Dimarino AM, Caplan AI, Bonfield TL. Mesenchymal stem cells in tissue
repair. Front Immunol 2013;4:201
6. Abdi R, Fiorina P, Adra CN, Atkinson M, Sayegh MH. Immunomodulation by
mesenchymal stem cells: a potential therapeutic strategy for type 1 diabetes.
Diabetes 2008;57:1759–1767
7. Nauta AJ, Fibbe WE. Immunomodulatory properties of mesenchymal stro-
mal cells. Blood 2007;110:3499–3506
8. Di Ianni M, Del Papa B, De Ioanni M, et al. Mesenchymal cells recruit and
regulate T regulatory cells. Exp Hematol 2008;36:309–318
9. Ghannam S, Pène J, Moquet-Torcy G, Jorgensen C, Yssel H. Mesenchymal
stem cells inhibit human Th17 cell differentiation and function and induce a T
regulatory cell phenotype [published correction appears in J Immunol 2013;191:
5777]. J Immunol 2010;185:302–312
10. Oh JY, Kim MK, Shin MS, et al. The anti-inflammatory and anti-angiogenic
role of mesenchymal stem cells in corneal wound healing following chemical
injury. Stem Cells 2008;26:1047–1055
11. Meisel R, Zibert A, Laryea M, Göbel U, Däubener W, Dilloo D. Human
bone marrow stromal cells inhibit allogeneic T-cell responses by indole-
amine 2,3-dioxygenase-mediated tryptophan degradation. Blood 2004;103:
4619–4621
12. Sato K, Ozaki K, Oh I, et al. Nitric oxide plays a critical role in sup-
pression of T-cell proliferation by mesenchymal stem cells. Blood 2007;109:
228–234
13. Chabannes D, Hill M, Merieau E, et al. A role for heme oxygenase-1 in the
immunosuppressive effect of adult rat and human mesenchymal stem cells.
Blood 2007;110:3691–3694
14. Ding Y, Xu D, Feng G, Bushell A, Muschel RJ, Wood KJ. Mesenchymal
stem cells prevent the rejection of fully allogenic islet grafts by the immu-
nosuppressive activity of matrix metalloproteinase-2 and -9. Diabetes 2009;
58:1797–1806
15. Lee RH, Seo MJ, Reger RL, et al. Multipotent stromal cells from human
marrow home to and promote repair of pancreatic islets and renal glo-
meruli in diabetic NOD/scid mice. Proc Natl Acad Sci U S A 2006;103:
17438–17443
16. Fiorina P, Jurewicz M, Augello A, et al. Immunomodulatory function of bone
marrow-derived mesenchymal stem cells in experimental autoimmune type 1
diabetes. J Immunol 2009;183:993–1004
17. Jurewicz M, Yang S, Augello A, et al. Congenic mesenchymal stem cell
therapy reverses hyperglycemia in experimental type 1 diabetes. Diabetes 2010;
59:3139–3147
18. Le Blanc K, Rasmusson I, Sundberg B, et al. Treatment of severe acute
graft-versus-host disease with third party haploidentical mesenchymal stem
cells. Lancet 2004;363:1439–1441
19. Le Blanc K, Frassoni F, Ball L, et al.; Developmental Committee of the
European Group for Blood and Marrow Transplantation. Mesenchymal stem cells

diabetes.diabetesjournals.org Carlsson and Associates 591

for treatment of steroid-resistant, severe, acute graft-versus-host disease:
a phase II study. Lancet 2008;371:1579–1586
20. von Bahr L, Sundberg B, Lönnies L, et al. Long-term complications, im-
munologic effects, and role of passage for outcome in mesenchymal stromal cell
therapy. Biol Blood Marrow Transplant 2012;18:557–564
21. von Bahr L, Batsis I, Moll G, et al. Analysis of tissues following
mesenchymal stromal cell therapy in humans indicates limited long-term
engraftment and no ectopic tissue formation. Stem Cells 2012;30:1575–
1578
22. Greenbaum CJ, Beam CA, Boulware D, et al.; Type 1 Diabetes TrialNet
Study Group. Fall in C-peptide during first 2 years from diagnosis: evidence of at

least two distinct phases from composite Type 1 Diabetes TrialNet data. Diabetes
2012;61:2066–2073
23. Dabelea D, Mayer-Davis EJ, Andrews JS, et al. Clinical evolution of beta cell
function in youth with diabetes: the SEARCH for Diabetes in Youth study. Dia-
betologia 2012;55:3359–3368
24. Moll G, Rasmusson-Duprez I, von Bahr L, et al. Are therapeutic human
mesenchymal stromal cells compatible with human blood? Stem Cells 2012;30:
1565–1574
25. Cramer C, Freisinger E, Jones RK, et al. Persistent high glucose concen-
trations alter the regenerative potential of mesenchymal stem cells. Stem Cells
Dev 2010;19:1875–1884

592 Mesenchymal Stromal Cells to Treat Type 1 Diabetes Diabetes Volume 64, February 2015