Rapid and selective mobilization of specific stem cell types after consumption of a polyphenol-rich extract from sea buckthorn berries (Hippophae) in healthy human subjects

Abstract

Purpose
The aim of this study was to evaluate the effects of a proanthocyanidin-rich extract of sea buckthorn berry (SBB-PE) on the numbers of various types of adult stem cells in the blood circulation of healthy human subjects.

Study design and methods
A randomized, double-blind, placebo-controlled, cross-over trial was conducted in 12 healthy subjects. Blood samples were taken immediately before and at 1 and 2 hours after consuming either placebo or 500 mg SBB-PE. Whole blood was used for immunophenotyping and flow cytometry to quantify the numbers of CD45dim CD34+ CD309+ and CD45dim CD34+ CD309− stem cells, CD45− CD31+ CD309+ endothelial stem cells, and CD45− CD90+ mesenchymal stem cells.

Results
Consumption of SBB-PE was associated with a rapid and highly selective mobilization of CD45dim CD34+ CD309− progenitor stem cells, CD45− CD31+ CD309+ endothelial stem cells, and CD45− CD90+ lymphocytoid mesenchymal stem cells. In contrast, only minor effects were seen for CD45dim CD34+ CD309+ pluripotential stem cells.

Conclusion
Consumption of SBB-PE resulted in selective mobilization of stem cell types involved in regenerative and reparative functions. These data may contribute to the understanding of the traditional uses of SBB for preventive health, regenerative health, and postponing the aging process.

Full text

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ORIGINAL RESEARCH
open access to scientific and medical research
Open Access Full Text Article
http://dx.doi.org/10.2147/CIA.S186893
Rapid and selective mobilization of specic stem
cell types after consumption of a polyphenol-rich
extract from sea buckthorn berries (Hippophae)
in healthy human subjects
Christian Drapeau1
Kathleen F Benson2
Gitte S Jensen2
1Biomx Stemceuticals, Austin, TX
78765, USA; 2NIS Labs, Klamath Falls,
OR 97601, USA
Purpose: The aim of this study was to evaluate the effects of a proanthocyanidin-rich extract
of sea buckthorn berry (SBB-PE) on the numbers of various types of adult stem cells in the
blood circulation of healthy human subjects.
Study design and methods: A randomized, double-blind, placebo-controlled, cross-over
trial was conducted in 12 healthy subjects. Blood samples were taken immediately before and
at 1 and 2 hours after consuming either placebo or 500 mg SBB-PE. Whole blood was used for
immunophenotyping and flow cytometry to quantify the numbers of CD45dim CD34+ CD309+
and CD45dim CD34+ CD309- stem cells, CD45- CD31+ CD309+ endothelial stem cells, and
CD45- CD90+ mesenchymal stem cells.
Results: Consumption of SBB-PE was associated with a rapid and highly selective mobiliza-
tion of CD45dim CD34+ CD309- progenitor stem cells, CD45- CD31+ CD309+ endothelial
stem cells, and CD45- CD90+ lymphocytoid mesenchymal stem cells. In contrast, only minor
effects were seen for CD45dim CD34+ CD309+ pluripotential stem cells.
Conclusion: Consumption of SBB-PE resulted in selective mobilization of stem cell types
involved in regenerative and reparative functions. These data may contribute to the understand-
ing of the traditional uses of SBB for preventive health, regenerative health, and postponing
the aging process.
Keywords: CD31, CD34, CD90, CD309, endothelial stem cells, mesenchymal stem cells
Introduction
Over the past decade, there is a growing interest among the aging adult population to
devote efforts into health maintenance instead of disease management.1,2 This trend
happens coincidentally with an overall aging of the world population due to decreasing
fertility rates combined with increased life expectancy,3 which is associated with a
growing disease burden.4 Overall, health maintenance or disease prevention involves
much lesser costs, and it is associated with much greater quality of life.5,6 This includes
the consumption of high-quality nutrients, probiotics, vitamin and mineral supplements,
botanical stem cell enhancers, and nutrient-dense fruits and berries such as amla, acai,
maqui berry, and goji berry.
Another plant with a long-standing traditional use in health maintenance, as well as
disease prevention and treatment, is sea buckthorn (SB). SB is a thorny nitrogen-fixing
deciduous shrub native to the cold and arid regions of North Western Europe and Cen-
tral Asia.7 Although its cultivation has spread as far as Canada8 and South America,9
Correspondence: Christian Drapeau
Biomx Stemceuticals, PO Box 49699,
Austin, TX 78765, USA
Email christian@biomxstemceuticals.com
Journal name: Clinical Interventions in Aging
Article Designation: Original Research
Year: 2019
Volume: 14
Running head verso: Drapeau et al
Running head recto: Drapeau et al
DOI: 186893
Point your SmartPhone at the code above. If you have a
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SB grows naturally at high altitudes (2,500–4,000 m) on the
Tibetan Plateau, Ladakh, Uttarakhand, Himachal Pradesh,
Jammu and Kashmir, Sikkim, and Arunachal Pradesh
regions.10 SB is highly resistant to extreme temperature and
conditions of drought and abundant rain, as well as high lev-
els of soil salinity and acidity.11,12 This is in part due to the fact
that the roots bear bulbs that contain nitrogen-fixing bacteria,
providing the development of an extensive root system in a
wide spectrum of climatic conditions.13 For this reason, SB
has been strategically propagated and cultivated in regions
such as Central China to prevent soil erosion, providing an
opportunity to harvest wild grown berries.
The small berries (sea buckthorn berry [SBB]), of 5–8 mm
in diameter, are spread over the length of thorny branches
covered with leaves. The berry consists of a dark brown
seed (23% w/w), 2.8–4.2 mm long, wrapped in a juicy flesh
(63% w/w) covered with a clear orange skin (7.8% w/w).14,15
The taste of SBB is unique and cannot be compared with any
other berry or fruit, owing to its aroma due to volatile com-
pounds such as ethyl dodecanoate, ethyl octanoate, decanol,
ethyl decanoate, and ethyl dodecanoate.16,17
Fruits, seeds, and leaves have all been shown to contain
a wide variety of compounds known for promoting health
maintenance.13,18 However, the actual chemical composition
of the berries and leaves greatly depends on the climatic con-
ditions, ripeness, and harvesting and processing methods.19
For example, berries grown at high altitude in harsh condi-
tions of seasonal drought and extreme temperatures were
documented to contain up to 10 times the amount of vitamin
C found in berries grown at lower altitudes.9 Interestingly,
SBB does not contain ascorbinase, which hydrolyses ascor-
bate, thus preserving vitamin C in the juice or dried berry.13
Overall, SBB is a good source of minerals, especially cal-
cium, phosphorous, iron, and potassium, as well as vitamins
C, B1, B2, E, A, and K.13,14,20–22 SBB is also a good source
of carotenoids, mainly β-carotene, lycopene, lutein, and
zeaxantin;14 phytosterols, mainly ergosterol, stigmasterol,
lanosterol, and amyrins;23 polyphenols, notably proantho-
cyanidins;9 and flavonoids, mainly quercetin, kaempferol,
myricetin, and isorhamnetin.22 Other bioactive compounds
also identified in SBB include hippophae cerebroside,
oleanolic acid, ursolic acid, 19-alpha-hydroxyursolic acid,
dulcioic acid, 5-hydroxymethyl-2-furancarboxaldehyde,
cirsiumaldehyde, octacosanoic acid, palmitic acid, and
1-O-hexadecanolenin.24
This blend of compounds provides SBB with obvious
antioxidant properties that have been widely documented and
even reported to be higher than 2,6-di-tert-butyl-p-hydroxy-
toluene (BHT) and tert-butyl-hydroxyanisole (BHA),
commonly used in food preservation.25,26 SBB extracts have
been reported to prevent plasma lipid peroxidation, cytotoxic-
ity, and even DNA damage.25,27
Interestingly, the scientific name for SB, Hippophae,
refers not to its physical characteristics but to its effect on
health. It is derived from the Greek words “hippo” (horse)
and “phae” (light) and essentially means “shining horse”. It is
reported that after abandoning horses wounded in battle in
a field of SB shrubs, Alexander the Great discovered on his
return from battle a herd of healthy horses with shiny coats,
a sign of health in a horse. SB was then brought to Greece
where it has been used for centuries as feed for horses.18
A similar story has been reported with Genghis Khan who,
the legend says, ordered his soldiers to harvest berries and
leaves to heal faster from battle wounds.
The health benefits of SBB have been recognized for more
than a thousand years in Tibetan, Mongolian, and Chinese
medicine. In China, its medicinal properties were recorded
in the Sibu Yidian from the Tang Dynasty and Jing Zhu Ben
Cao from the Qing Dynasty. In Tibet, references to SBB
were found in medicinal texts such as “rGyud-bzi” (The Four
Books of Pharmacopeia) at the times of the Tang Dynasty
(618–907AD).28,29 In Tibetan and Mongolian traditional
medicine, SBB has been used to improve blood circulation
and to treat a long list of ailments including lung conditions
such as asthma, diabetes, stomach ulcers, cancer, wounds,
metabolic disorders, and inflammation.9,18,30
While some of the benefits on cardiovascular health and
diabetes have been corroborated by Western science, few
mechanisms of action aside from SBB’s antioxidant proper-
ties have been proposed to explain its wide range of health
benefits. Table 1 lists the documented benefits of SB.31–60
Other plants associated with wide ranges of health benefits
have been previously reported to act by triggering the release
of stem cells from the bone marrow.61–63 By mobilizing more
stem cells to enter the blood circulation, more stem cells are
available to participate in the process of tissue repair in the
body. Given the wide range of benefits associated with
the use of SBB, in this study, we investigated the effect of
the consumption of a proanthocyanidin-rich extract of SBB
(SBB-PE) on stem cell mobilization.
Materials and methods
Study design
The clinical study followed a randomized, double-blinded,
placebo-controlled crossover design. Twelve people were
screened and enrolled after providing written informed
consent, and this study was conducted in accordance with
the Declaration of Helsinki and approved by the Sky Lakes

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Table 1 Biological activities associated with SBBs
Applications Health benets Mechanism of action Reference
Cardiovascular Inhibitory effect of SBB avonoids on NF-kappa B activation in
cardiomyocytes
Suggested antioxidant properties 31,32
SB oil affects lipid metabolism in atherosclerosis Mechanism unknown 33,34
SBB antioxidants reduced risk factors for coronary heart
disease in humans
Suggested antioxidant properties 35
SBB reduced the oxidative stress in human plasma Suggested antioxidant properties 25
SBB reduced blood pressure, plasma lipids, and increased
ventricular capillary density
Mechanism unknown 36
SBB avones prevented in vivo thrombogenesis Inhibition of platelet aggregation 37
SB seed avones suppressed hypertension, hyperinsulinemia,
and dyslipidemia
In part by improving insulin sensitivity and
blocking angiotensin II
38
Gastric ulcer SBB extract reduced ulcer number and size May be by increasing glutathione level 39,40
SB oil reduced ulcer Mechanism unknown 41
SB oil reduced ulcer in dogs Mechanism unknown 42
Antitumor,
anticarcinogenic
SB oil showed anticancer properties
Isorhamnetin, a SBB avone, had antiproliferative activity
against lung cancer
Suggested antioxidant properties
Upregulation of apoptotic genes
43–45
Isorhamnetin suppressed colon cancer cell growth Inhibition of PI3K-Akt-mTOR pathway 46
SBB extract showed antitumor activity in in vivo two-stage
carcinogenesis test in mice
Mechanism unknown 47
SBB polysaccharide inhibited Lewis lung carcinoma Through immunostimulation 48
Obesity SB leaves reduced visceral fat in obese mice Suggested antioxidant properties 49,50
SB leaves reduced adipogenic and lipogenic gene expression Upregulation of PPAR; reduction in
acetyl-CoA carboxylase
51
Diabetes SB seed extract had hypoglycemic effect in STZ-treated mice Mechanism unknown 52
SB pulp reduced glycemia, restored pancreatic beta cells in
STZ-treated mice
Mechanism unknown 53
SB leaf extract inhibited alpha-glucosidase Inhibition of alpha-glucosidase 54
SBB lowered fasting and postprandial glycemia by increasing
insulin secretion
Mechanism unknown 55
SBB extract suppressed postprandial peak insulin response and
stabilized postprandial hyperglycemia
Mechanism unknown 56
SB fruit oil alleviated type 2 diabetes Through PI3K/Akt signaling pathway 57
Wound healing SB avones promoted wound healing Mechanism unknown 58
SB leaf extract accelerated would healing Upregulation of VEGF and angiogenesis 59
SB seed oil help heal burn wounds Enhance microcirculation and tissue
regeneration
60
Abbreviations: SB, sea buckthorn; SBB, sea buckthorn berry; STZ, streptozotocin.
Medical Center Institutional Review Board (FWA 2603).
The trial is registered at ClinicalTrials.gov (ClinicalTrials.gov
Identifier: NCT03388073). The study population included
eight females and four males with an average age of
49.3±21 years and a body mass index (BMI) between 20.0 and
34.6 kg/m2 (Table 2), with no known chronic illness, frequent
recreational drug use, impaired digestive function (including
previous major gastrointestinal surgery), or known allergies
to berry products. The study participants were scheduled for
two clinic visits at least 1 week apart. The visits were always
scheduled at the same time of the day for each person, the
same day of the week, and always during the morning hours
of 7–11 am to minimize the effect of circadian fluctuations.
Since there is a well-documented interference from exercise64
and stress65–68 with the release vs homing of lymphocytes, the
study environment was managed to minimize the physical
and mental stress before and during testing. On arrival to each
clinic visit, study participants completed a questionnaire to
help monitor exceptional circumstances that might be affect-
ing the stress level of that person on that day. Predetermined
criteria for re-scheduling a visit included sleep deprivation
and acute anxiety. After completing the questionnaire,

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volunteers were instructed to remain calm and inactive for
3 hours, comfortably seated in a chair. After the first hour,
the baseline blood sample was drawn. Immediately after the
baseline sample was drawn, an encapsulated test product was
provided with water and consumed in the presence of the
clinic staff. Blood samples were drawn at 1 and 2 hours after
ingestion of the test product or placebo. At each blood draw,
6 mL of blood was drawn into sodium heparin vacutainer
tubes for subsequent immunostaining. The heparin vials were
placed on a rocker until staining, which was initiated within
the hour of each blood draw.
Consumables
A proanthocyanidin-rich water extract of whole SBBs
(Puredia, Irvine, CA, USA) was encapsulated at NIS Labs
with 500 mg/dose. Placebo capsules were prepared using
rice flour. Study participants and clinic staff were blinded to
the consumables. Randomization was performed following
the Latin Square design, such that half the study participants
received the active test product at the first visit and placebo at
the second visit, and the other half of the study participants
received products in the reverse sequence.
Stem cell evaluation by ow cytometry
For each blood draw, triplicate samples of 100 µL of heparin-
ized whole blood was stained using the following four-color
immunostaining panel: CD31-FITC, CD34-PerCP, CD45-
PO, and CD133-PE. For eight of the study participants, a
fifth color was added: CD90-v421. Staining was performed
as recommended by Thermo Fisher Scientific (Waltham,
MA, USA) for whole blood staining followed by a “no-wash”
procedure involving Cal-Lyse® fixation of white blood cells
and lysing of red blood cells. In brief, samples were stained in
the dark at room temperature for 15 minutes followed by the
addition of 100 µL of Cal-Lyse® Lysing solution and fixation
for 10 minutes at room temperature. Red blood cells were
then lysed by the addition of 1 mL of deionized water and
further 10 minutes incubation in the dark at room tempera-
ture. Samples were stored at 4°C in the dark and acquired by
flow cytometry within 24 hours using an acoustic-focusing
Attune™ flow cytometer (Thermo Fisher Scientific). Files
of 300,000–600,000 events were collected for each triplicate
sample. Data on stem cell numbers were analyzed by the
Attune software (Thermo Fisher Scientific) that provides
results as cell per microliter of sample and compensated
for the dilution factor that was part of the immunostaining
protocol, so the results were converted to stem cell numbers
per microliter of whole blood.
Statistical analyses
Average and SD for each data set were calculated using
Excel (Microsoft Corporation, Redmond, WA, USA). The
statistical significance of post-consumption changes from
baseline to later assessments was evaluated by between-
treatment analysis using within-subject analysis and the
two-tailed paired t-test. Statistical significance was indicated
by P,0.05, and a high level of significance was indicated
by P,0.01.
Results
Study population and compliance
The demographic characteristics for the study participants
are shown in Table 2. All 12 study participants completed
the study participation with full compliance, including
adhering to similar routines and food for 12 hours prior to
arrival on both clinic days, remaining calm and unstressed
during the 3-hour clinic visits, consuming test products with
water as instructed, and allowing the three blood draws at
each visit.
Post-consumption changes in circulating
stem cells
Each blood sample was used to perform immunostaining and
flow cytometry to evaluate the post-consumption changes to
the numbers of three different subtypes of circulating stem
cells. For eight of the study participants, post-consumption
changes to a subset of mesenchymal stem cells (MSCs),
Table 2 Demographics of the study population
Study participants Gender Age (years) BMI (kg/m2)
P01 F 56 32.5
P02 F 62 23.6
P03 F 62 30.8
P04 F 32 23.5
P05 M 28 22.1
P06 M 59 29.8
P07 M 49 31.7
P08 F 61 24.5
P09 M 70 21.0
P10 F 56 22.0
P11 F 55 34.6
P12 F 51 23.3
Average 53.4 26.6
SD 12.3 4.9
Range 28–70 21.0–34.6
Abbreviations: BMI, body mass index; F, female; M, male.

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identified in the absence of CD45 and the expression of CD90
on cells within the lymphocyte gate were also evaluated.
Given interindividual variations in the time course of
the mobilizing response following the consumption of
SBB-PE, some individuals showed a greater response at
1 hour, whereas others showed a greater response at 2 hours.
Therefore, simply averaging the responses at the respective
time points may underestimate the actual response and pro-
vide greater SDs. For this reason, an additional analysis was
performed using the data from the time point that showed
the greatest response.
Changes in the number of stem cells
expressing CD34
CD34 is a transmembrane protein that is expressed almost
exclusively on certain types of stem cells. Lymphocytoid
CD34+ stem cells are also showing a low level of expres-
sion of the protein tyrosine phosphatase receptor type C
enzyme, CD45 (CD45dim). This is in contrast to mature
hematopoietic cells that show a high level of cell surface
CD45 expression69,70 and to other types of stem cells that are
completely negative for CD45 (CD45-).71 The changes in
CD45dim CD34+ stem cell numbers were analyzed to see
whether the effects of consuming SBB-PE altered the levels
of CD34+ stem cells in the circulation.
The CD45dim CD34+ stem cell population is further
divided into two subtypes, based on whether the cells express
the CD309 antigen, a transmembrane tyrosine kinase also
known as vascular endothelial growth factor receptor-2
(VEGFR-2) and kinase insert domain-containing receptor
(KDR; CD309). The presence of CD309 on stem cells has
been associated with a more pluripotent (ie, undifferenti-
ated) phenotype.72 Furthermore, the expression of CD309
on CD34+ cells in the circulation has been implicated with
vascular maintenance and repair.73 The absence of CD309
on CD34+ stem cells has been associated with a progenitor
phenotype.74 Consumption of SBB-PE triggered a selective
mobilization of CD45dim CD34+ CD309- cells, in contrast
to no changes to CD45dim CD34+ CD309+ pluripotential
stem cells (Figure 1). When considering the greatest response
at either 1 or 2 hours, the number of circulating CD45dim
CD34+ CD309- cells and CD45dim CD34+ CD309+ cells
increased by 24.2%±5.3% (P,0.001) and 19.5%±7.0%
(P,0.016), respectively (Figure 4).
Changes in endothelial stem cells
The immunophenotyping also included the assessment of
circulating endothelial stem cells with the phenotype of
CD45- CD31+ CD309+.75 Endothelial stem cells have been
shown to be rapidly mobilized following acute myocardial
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Figure 1 Changes in CD45dim CD34+ stem cells within 2 hours of consuming SBB-PE vs placebo.
Notes: The results are shown as the average±SEM of the individual percent changes from baseline after consuming either SBB-PE (solid line) or placebo (dashed line). (A) For
the CD45dim CD34+ CD309- lymphocytes, the difference between the treatments did not reach statistical signicance (P,0.17); however, the increase in CD45dim CD34+
CD309- stem cells at 2 hours after consuming SBB-PE was highly signicant when comparing to baseline (**P,0.007). (B) In contrast, there were no signicant changes in
the CD45dim CD34+ CD309+ stem cells after consuming either SBB-PE or placebo.
Abbreviations: SBB-PE, proanthocyanidin-rich extract of sea buckthorn berry; SEM, standard error of the mean.

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Drapeau et al
infarction76,77 and are being actively researched for use in
regenerative medicine. Consumption of SBB-PE triggered
mobilization of CD45- CD31+ CD309+ endothelial stem
cells, in contrast to placebo where a mild reduction was seen,
likely part of the normal circadian rhythm for this cell type.
The difference in the numbers of circulating CD45- CD31+
CD309+ endothelial stem cells after consumption of SBB-PE
vs placebo was statistically significant at 1 hour (P,0.04)
and after 2 hours (P,0.05; Figure 2). When considering the
greatest response at either 60 or 120 minutes, the number
of circulating CD45- CD31+ CD309+ cells increased by
33.4%±10.2% (P,0.007; Figure 4).
Changes in MSCs
For eight of the twelve study participants, the changes in
numbers of lymphocytoid stem cells that expressed the
mesenchymal stem cell marker CD90 was evaluated. The
lymphocytoid stem cells that expressed the mesenchymal
stem cell marker CD90 were negative for CD45. Post-
consumption changes showed an increase in CD45- CD90+
lymphocytoid stem cells at 1 hour and 2 hours after consum-
ing SBB, in contrast to only minor changes after consuming
placebo. The increase at 2 hours, compared to baseline,
reached a borderline statistical trend (P,0.11) (Figure 3).
When considering the greatest response at either 60 or 120
minutes, the number of circulating CD45- CD90+ lym-
phocytoid stem cells increased by 20.8 ± 5.7% (P,0.016)
(Figure 4).
Discussion
The migration of stem cells, seeking sites in need of repair,
is crucial for the processes involved in ongoing normal
maintenance and rejuvenation of healthy tissue, as well as
for specific repair and healing of injured tissue. Therefore,
the documentation of stem cell mobilization after consuming
a botanical SBB-PE suggests a mechanism for the traditional
uses of SBB in folk medicine. The basic definition of a
stem cell is an undifferentiated cell that can self-replicate
and also can develop into any one of various kinds of cells
(such as blood cells, skin cells, nerve cells, etc.). There are
multiple types of stem cells, each having distinct phenotypes.
Pluripotential stem cells have the capacity to differentiate
into hematopoietic and non-hematopoietic lineages. MSCs
(also known as multipotent mesenchymal stromal cells) are
non-hematopoietic and possess the capacity for self-renewal
and multi-lineage differentiation, including osteoblasts,
chondrocytes, neurons, muscle cells, adipocytes, and insulin-
expressing cells in pancreatic islets. MSCs have also been
demonstrated to have unique immunomodulatory properties
including their ability to reduce immune cell infiltration and
to modulate inflammation.
The response to consuming SBB-PE was selective and
involved specific types of stem cells, whereas the numbers
of other types of stem cells in the blood circulation did not
change. The CD45dim CD34+ CD309- cells, CD45dim
CD34+ CD309+ cells, and the CD45- CD31+ CD309+
endothelial stem cells showed significant mobilization
above placebo within 2 hours. Regarding their regenerative
properties, the number of circulating stem cells has been
documented to be a critical parameter. When the number of
circulating endothelial progenitor cells was quantified in the
blood of 509 individuals at risk for cardiovascular disease and
the incidence of cardiovascular events in these individuals
was monitored for 1 year, a significantly greater number of
events took place in the individuals having fewer circulating
stem cells. In this study, the number of circulating stem cells
was documented as one of the best predictor of cardiovascular
health.78 Likewise, following acute myocardial infarction,
individuals with a higher baseline number of circulating
stem cells showed a greater ejection fraction 6 months
later.79 A link between a lower number of circulating stem
cells and the development of degenerative diseases has
been established with diabetes,80 cardiovascular diseases,81
atherosclerosis,82,83 Alzheimer’s disease,84,85 rheumatoid
arthritis,86,87 pulmonary diseases,88,89 erectile dysfunction,90,91
and muscular dystrophy.92
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Figure 2 Changes in CD45- CD31+ CD309+ endothelial stem cells within 2 hours
of consuming SBB-PE vs placebo.
Notes: The results are shown as the average±SEM of the individual percent changes
from baseline after consuming either SBB-PE (solid line) or placebo (dashed line).
There was no signicant difference between the treatments; however, the increase
in CD45- CD31+ CD309+ endothelial stem cells at 1 and 2 hours after consuming
SBB-PE was statistically signicant when comparing to baseline (*P,0.05).
Abbreviations: SBB-PE, proanthocyanidin-rich extract of sea buckthorn berry;
SEM, standard error of the mean.

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Drapeau et al
Furthermore, increasing the number of circulating stem
cells has been documented to enhance tissue repair or to
improve the course of disease formation in cases of acute
myocardial infarction,93,94 stroke,95 bone fracture,96 muscle
injury,97 spinal cord injury,98 diabetic wound healing,99 and
inner ear damage,100 to name a few. Stem cell mobilization
using an extract of the cyanophyta species Aphanizomenon
flos-aquae was documented to improve cases of severe
cardiomyopathy, stroke, diabetes, rheumatoid arthritis,
kidney failure, and Parkinson’s disease.62 An extract of
Rehmannia glutinosa was also shown to trigger stem cell
mobilization via a CXCR4-dependent mechanism and to
improve the outcome of myocardial infarction.101 Altogether,
these data suggest that SBB-PE could be a novel natural stem
cell mobilizer with the potential of improving the course of
several degenerative diseases.
We have shown here that consuming SBB-PE leads to
selective increase in circulating CD45- CD90+ lymphocytes.
Stem cells were also shown to play an important paracrine
role, which includes cross-talk with other cell types and
profound regulating effects such as reducing inflammation,102
which can play an important role in wound healing. MSCs
expressing CD90 are capable of suppressing inflammatory
conditions by various mechanisms. This has been well
documented in various types of tissue models, including
dental pulp stem cells that have shown immunomodulatory
effects where specific inflammatory macrophage activity
and cytokine profile are suppressed.103 MSCs also support a
shift in macrophage polarization from the highly inflamma-
tory “M1” toward the anti-inflammatory “M2” type, which
is known to facilitate wound healing and is also associated
with changes in metabolic health and glucose metabolism.104
Thus, reparative effects of stem cells in, for example, dia-
betes may involve repair through regeneration of pancreatic
beta-cells, but may also involve an immunological shift in
macrophage polarization, positively supporting an improved
metabolic health.
Resolution of inflammation is essential to successful
healing of wounds and damaged tissue, and chronic inflam-
mation can lead to poor healing outcomes.105 The plasticity
within the stem cell hierarchy is important and even though
the hierarchy places pluripotential stem cells at the top, with
35
25
CD45– CD90+ lymphocytes
15
Percent change
5
Baseline 1 hour 2 hours
(*)
–5
–15
SBB-PE
Placebo
Figure 3 Changes in circulating CD90+ mesenchymal stem cell subpopulations.
Notes: The results are shown as the average±SEM of the individual percent changes
from baseline after consuming either SBB-PE (solid line) or placebo (dashed line).
For the CD45- CD90+ lymphocytes, the difference between the treatments
did not reach statistical signicance; however, the increase in CD45dim CD90+
mesenchymal stem cells at 2 hours after consuming SBB-PE reached a statistical
trend (*P,0.1).
Abbreviations: SBB-PE, proanthocyanidin-rich extract of sea buckthorn berry;
SEM, standard error of the mean.

&'±&'O\PSKRF\WHV
3
&'GLP&'&' 3
&'±&'&' 3
&'GLP&'&'± 3
       

3HUFHQWPD[LPXPFKDQJHFRPSDUHGWREDVHOLQH
6HOHFWLYHPRELOL]DWLRQIRUGLIIHUHQWVWHPFHOOW\SHV
Figure 4 The maximum change (1 or 2 hours) after consumption of SBB-PE.
Notes: The maximum changes in stem cell numbers, whether seen at 1 or 2 hours after consumption of SBB-PE, were adjusted for the matching placebo response for each
person, and the results are represented as average±SEM. The analysis of the acute effects on stem cell mobilization reduced the individual variations and showed signicant
changes above placebo.
Abbreviations: SBB-PE, proanthocyanidin-rich extract of sea buckthorn berry; SEM, standard error of the mean.

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endothelial, mesenchymal, and hematopoietic stem cells at a
further differentiated state, the possibility exists to revert back
to the pluripotent state.106 The ability of MSCs to modulate
the inflammatory response in wounds includes both a reduc-
tion in infiltration of inflammatory cells and a reduction in
pro-inflammatory cytokines such as interleukin (IL)-1 and
tumor necrosis factor (TNF)-alpha. This ability also supports
their favorable effect on the healing response, and there is an
increasing interest in non-invasive use of plant extract for
regenerative medicine.107 The clinical importance of stem
cell mobilization in reparative functions is well documented
for improvement in diabetic conditions108 and cardiovascular
repair after infarct,109 and therefore, natural stem cell mobiliz-
ers such as SBB-PE could be effective tools to improve overall
health and to accelerate the healing process by supporting the
actual process of tissue repair and reducing inflammation.
Conclusion
By documenting the ability of SBB-PE to support stem cell
mobilization and to increase the number of circulating stem
cells, we have uncovered a new mechanism of action behind
many of the health benefits that have been historically associ-
ated with SBB, as a part of its use in Tibetan, Mongolian, and
Chinese traditional medicine. Once mobilized, bone marrow
stem cells can participate in the process of tissue repair and
modulate local inflammation, supporting the use of SBB-PE
in overall health maintenance.
Data sharing statement
The authors do not plan to share individual de-identified par-
ticipant data beyond the data presentation in this manuscript.
Acknowledgments
This study was conducted at NIS Labs, an independent
contract research organization that specializes in natural
products research. The study was co-sponsored by Biomx
Stemceuticals LLC and NIS Labs R&D, Inc.
Author contributions
CD and GSJ planned the testing of sea buckthorn for stem cell
effects. CD researched the historical use and current scientific
knowledge about sea buckthorn. GSJ designed and oversaw
the clinical study. KFB conducted the stem cell staining and
flow cytometry. KFB and GSJ analyzed the data and inter-
preted the results. CD and GSJ co-wrote the manuscript. All
authors contributed to data analysis, drafting or revising the
article, gave final approval of the version to be published, and
agree to be accountable for all aspects of the work.
Disclosure
CD is the co-founder and executive director of Biomx
StemCeuticals LLC, and GSJ is the research director for
NIS Labs. The authors report no other conflicts of interest
in this work.
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