Mesenchymal Stem Cell-Conditioned Medium (Secretome) in Skin Aging A Systematic Review

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Mesenchymal Stem Cells-Conditioned Medium (SECRETOME) in Skin Aging:

A Systematic Review
Article in International Journal for Pharmaceutical Research Scholars · June 2021

DOI: 10.31838/ijpr/2021.13.02.020
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DOI: https://doi.org/10.31838/ijpr/2021.13.02.020
Review Article
Mesenchymal Stem Cells-Conditioned Medium

(SECRETOME) in Skin Aging: A Systematic Review
WINAWATI EKA PUTRI1,2,3, ANANG ENDARYANTO2, FEDIK ABDUL RANTAM4,5, CITA ROSITA SIGIT
PRAKOESWA2
1
Post Graduate Doctoral Program, Faculty of Medicine, Universitas Airlangga, Indonesia.
2
Airlangga University Faculty of Medicine, Dermatology and Venereology, Surabaya, Indonesia.
3
University of Nahdlatul Ulama Surabaya, Dermatology and Venereology, Surabaya, Indonesia.
4
Institute of Tropical Disease, Airlangga University, Stem Cell Laboratory, Surabaya, Indonesia.
5
Department of Microbiology, Faculty of Veterinary Medicine, Airlangga University, Virology and
Immunology Laboratory, Surabaya, Indonesia.
*Corresponding Author
Email ID: cita-rosita@fk.unair.ac.id
Received: 04.11.20, Revised: 28.12.20, Accepted: 21.01.21
ABSTRACT
Background: The skin aging is the most important factor that constitutes the general "well-being" and perception
of "health" in humans. The mesenchymal stem cells (MSCs) have a therapeutic effect on anti-apoptosis, angiogenic,
immunomodulatory and chemo-existing activity, especially in its treatment. However, the use of mesenchymal
stem cell-conditioned medium (MSC-CM) as skin aging therapy requires further investigation.
Methods: The systematic literature search have the following keywords; conditioned media or conditioned
medium or secretome as well as photoaging or skin aging. A total of 283 articles were reviewed from Pubmed,
Wiley Online Library, Science Direct and The Cochrane Library, and only 11 articles were relevant for this
systematic review.
Results: The results show that Secretome is promising in improving the skin aging process. However, due to the
high heterogeneity, a meta-analysis cannot be performed.
Conclusion: The use of secretome was promising in improving skin aging process, as shown by the available
preclinical studies. However, further clinical studies are needed to confirm the benefits and effects of secretome.
Keywords: mesenchymal stem cell, secretome, conditioned medium, skin aging.
INTRODUCTION various types of cells such as adipocytes,

Skin aging is a complex biological process that is osteoblasts, chondrocytes, fibroblasts, and
influenced by a combination of intrinsic and myoblasts. There are many types of MSC, which
extrinsic factors1. Furthermore, it is associated with includes bone marrow stem cell (BMSC), umbilical
decreased skin function, increased skin fragility, cord (UC) -MSC, placenta (P) -MSC, umbilical cord
and impared skin wound healing. In contrast to blood (UCB) -MSC, amniotic fluid (AF) -MSC, and
thin, atrophic, finely wrinkled and dry intrinsically adipose stem cell (ASC)8. In addition, Mesenchymal
aged skin, premature photoaged skin typically stem cell produces various secreted factors like
shows thickened epidermis, mottled discoloration, cytokines, growth factors and chemokines, which
deep wrinkles, laxity, dullness and roughness 1–5. may trigger intracellular mechanism. The main
The increase in the aging of the population and the functions of MSC are tissue replacement through
changes in skin aging that affect self-esteem leads multipotent differentiation, immunomodulatory and
many anti-aging therapies to be developed 6,7. anti-inflammatory effects, and molecular secretion,
Stem cells (SC) therapy, which contains different which helps tissue repair9,10. This SC is a good
types of growth factors, is commonly used for skin choice for regenerative medicine because it is easily
aging. Furthermore, they are unique populations of obtained (bone marrow, adipose and UCB) and
cells that are undifferentiated, able to renew has low immunogenicity9.
themselves, and differentiate into different cell In recent years, conditioned medium (CM) or SC-
lineage. The mesenchymal SC (MSC) is a derived secretome has received more attention in
multipotent stromal cell that can differentiate into the field of regenerative medicine and has generally
613| International Journal of Pharmaceutical Research | Apr - Jun 2021 | Vol 13 | Issue 2
Winawati Eka Putri et al / Mesenchymal Stem Cells-Conditioned Medium (SECRETOME) in Skin Aging: A
Systematic Review
shown good results. The use of secretome has benefits of MSC-CM or secretome for skin aging
several advantages when compared to SC, as CM therapy.
can be manufactured, freeze-dried, packaged, and
transported more easily. Moreover, as it is devoid of METHODS
cells, there is no need to match the donor and the Eligibility criteria
recipient to avoid rejection problems11. The The inclusion criteria used an experimental study in
secretome contains many growth factor, cytokines, English with human and animal study groups with
chemokines, angiogenic factors, microvesicle and skin aging (intrinsic and extrinsic factors), given the
exosome. Therefore, SC-derived CM have a intervention in the form of the application of MSC-
promising prospect to be produced as CM/secretome. The expected outcome was the
pharmaceuticals for regenerative medicine11,12. In clinical and histological outcome as the primary
addition, its potential role as a cosmetic ingredient outcome. Non-English studies, duplicates, review
is being explored13. studies, and irrelevant articles as exclusion criteria.
A previous in vitro study showed that medium Literature search and study selection
conditioned with adipose stem cells (ASC-CM) can The integrated search process was carried out in
increase the expression of collagen type I mRNA, accordance with the instructions of the Preferred
type III collagen and elastin in senescence human Reporting Items for Systematic Reviews and Meta-
dermal fibroblast (HDF). However, this ability were Analyzes (PRISMA) guidelines. The article was
reduced, as the passage of HDF increased14. identified from searches of PubMed (MEDLINE), the
Another study conducted by Li et al showed anti Cochrane Library, Science Direct, and Wiley Online
photoaging activities of this ASC-CM on human Library on June 9th, 2020. The terms used as the
keratinocytes and fibroblasts exposed to UVB light. search keywords contains at least two words:
Inhibition of phosphorylation of the MAPK/ AP-1 “conditioned media” or “conditioned medium” or
pathway, decrease in NF-Kβ activation and secretome and skin aging or photoaging. The
downregulation of HO-1 activation as well as authors (W.E.P and C.R.S.P) then reviewed the
increase in expression of TGF-β and Smad 2/3 feasibility of the article on the basis of inclusion and
proteins were reported15. Therefore, the purpose of exclusion criteria, the due diligence was conducted
this study literature is to know the effects and by the author in a discussion and independent
manner.
Winawati Eka Putri et al / Mesenchymal Stem Cells-Conditioned Medium (SECRETOME) in Skin Aging: A
Systematic Review
Total articles from database

(n = 283)
Exclude based title and abstract

(n = 268)
Title and Abstract relevant

(n = 22)
Exclude article cause inclusion criteria

(n = 4)
Articles full text and relevant

(n = 18)
Exclude in vitro study

(n = 7)
Articles in the systematic review

(n = 11)
Fig.1: Prisma Flowchart
Methodological quality assessment and risk of animals or human in the included studies; type and
bias specific donor of MSCs; the isolation process for the
Two authors (W.E.P and C.R.S.P) in determining the CM; interventions; comparison; duration of follow-
assessment of methodological quality and risk of up; main outcome for the in vivo studies and the
bias by combining animal testing guidelines: results; any significant differences from control or
Reporting on in vivo Experiments (ARRIVE) baseline; and other outcomes. For in vivo studies,
guidelines with Consolidating Reporting of Trials16. any adverse reactions were reviewed, clinical
Data extraction and synthesis outcomes, and histological outcomes. The authors
The data extraction was performed by two authors agreed to classify types of MSCs into BMSC, ASC,
(W.E.P and C.R.S.P) that were independent of each UCB-MSC, AF-MSC and AMSC. The data collection
study and were in agreement with all included of in vivo study and clinical study outcomes are
studies. Then, the following data were extracted: shown in Table 1. A meta-analysis could not be
study design, human model and type of animal carried out due to high heterogeneity data.
model for in vivo studies; establishment process for
Winawati Eka Putri et al / Mesenchymal Stem Cells-Conditioned Medium (SECRETOME) in Skin Aging: A Systematic Review
Table 1: The studies overview

Type of Level Type of
Author Population Sample Intervention Controlled
MSC CM Study
Sohn et EPC CM Human Clinical 25 Korean women (29-69 years old) with mild to 5% EPC-CM was applied twice a day on N/A
al17 study moderate wrinkles. both sides of the face for 4 weeks.
NHDF cells were pretreated with each

hMSCs were differentiated to EPCs for 10–21 days. CM for 24 h, followed by exposure to
Conditioned medium was also collected from 600 µm H2O2 for 24 h. NHDF cells were exposed to
In vitro undifferentiated MSC. 600 µm H2O2 for 24 h.
Prakoes AMSC CM Human Clinical 48 subjects aged 41-60 years old and receive 24 subjects were treated with microneedling24 subjects were treated with
wa et study priming with 0,025% tretinoin cream for 2 weeks. plus 3 mL of AMSC-CM for 3 times with microneedling plus 3 mL
al18 an interval of 2 weeks. of NS; for 3 times with an
interval of 2 weeks.

MSC CM Study
Kim et AD, BM, CM Human Clinical 22 volunteers (18–55 years-old women) USC-CM in cream base were treated N/A
al19 and study daily to their skin.
UCB
Conditioned media (CM) of MSCs and HDFs HDFs (1×103 cells/well) were seeded in
were collected. The conditioned media were 96-well plates and cultured for 24 h in KSB-2 media.
In vitro measured with GDF-11 ELISA kit. KSB-3 medium. After washing, the
medium was replaced by HDF-CM, AD-
MSC-CM and UCB-CM.

MSC CM Study
Yan Xu ASCs SC Human Clinical 18 young volunteers were randomly divided into The CM of ASC or PSC was dissolved Injected with HA
et al20 and PCs Study 3 groups with 6 in each group: ASC-CM group, into injectable hyaluronic acid (HA)
PSC-CM group, and control group.
100 mL of adipose tissue was harvested from a

45-year-old female cosmetic surgery patient. Characterization of ASC and PSC with
FACS analysis and multipotency
analysis. N/A
In vitro The final concentration from ASC-CM and PSC-
CM were 70 mL of 5.989±0.07 mg/mL in freeze
dry powder. Characterization of CM with MALDI-
TOF/TOF analysis.
Yang Xu DA CM Mice In vivo 8 immunodeficient nude BALB/C mice (female, 8 200 µL of 10-fold-concentrated DA-CM 200 µL of 10-fold-
et al21 weeks old): UVB induced photoaging mice was subcutaneously injected at two concentrated DMEM was
(5x/weeks for 8 weeks). places on one side of dorsal skin, once subcutaneously injected at
a week for a total of three times. other side as control,
Adipose tissue was taken by liposuction from once a week for a total of
healthy adult. three times.
HDFs derived from the foreskin of a 20-year-old DA-CM-treated HDFs (HDFs cultured in
donor. DACM),

MSC CM Study
It was irradiated with UVB source, with dosage and DA-CM-treated SIPS-HDFs (HDFs HDFs (HDFs cultured in
10 mJ/cm2, once a day for 5 days. cultured in serum-free DMEM), SIPS-
DA-CM and exposed to UVB HDFs
irradiation). (HDFs cultured in serum-
In vitro free DMEM and exposed
to UVB
irradiation).
El- AF-MSC CM Human Clinical 10 volunteers (3 males and 4 females) age 41- 5 sessions of skin needling, 2 weeks Left side, only skin
Domyati Study 60 years old with facial aging apart, AF-MSC-CM was added topically needling.
et al22 to the right side only.
Lee et ESC- CM Human Clinical 25 participants were 41-64 years old and had 5 treatment sessions of microneedle with 5 treatment sessions of
al23 EPC study Fitzpatrick Skin Type III or IV. hESC-EPC CM were repeated at 2-week microneedle with saline
intervals. were repeated at 2-week
intervals.
Amirthali BMSC CM Mice In vivo 6 to 8 weeks old nude mice (NU/ NU) All mice were irradiated with UVB at a Not irradiated with UVB
ngam et dose of 150 mJ/cm2, once daily, for
al13 seven days and given CM.
HFF cells were photo-damaged by UVB HFF treated with 0.25%, 0.5% and 1%
In vitro irradiation (300 mJ/cm2). for 48 h.
Kim et ASC CM Human Clinical Female adults aged 30–60 years were selected. Cream containing 3D cultured ADMSCs-
al19 Study CM was applied on:
1. Left lower forearm
2. Left upper forearm after treated with SLS
3. Face
HDF was treated with 2D or 3D cultured

ASC-CM
HDF were obtained from males of 20 years old

or under Negative control was
In vitro cultured with basal
medium without serum.
Positive control was
cultured in a basal

MSC CM Study
medium supplemented
with 0.04%.
Wang et ASC Protei Human Clinical 30 females between 40 and 63 years (skin type Protein extracts from ADSC-CM were Ultrapure water was
al24 n Study III and IV), applied via microneedles into the skin applied via microneedles
extrac with interval 2 weeks (W0, W2, W4, W6, in control group.
t of W8, W10).
CM
Kwon et BMSC CM Mice In vivo 48 photoaged female SKH-1 hairless mice, 6 Topical BMSC-CM was applied on Vehicle solution
al25 weeks old dorsal skin mice 3x/week for 8 weeks. (polyethylene glycol:
ethanol 7:3) was applied
on dorsal skin mice
3x/week for 8 weeks
Human dermal fibroblasts Treated by MSC-CM (0,1%, 1% and
In vitro 10%) for 24 and 48 h NA
Table 2: In vivo studies and clinical studies results

Assessment
Significant difference Significant difference Other Other outcome
Author of main Main outcome measure(s) Results
from baseline between groups evaluation measure(s)
outcome
Sohn et al17 4 weeks Crow’s feet. The levation of Improved significantly during Yes (p<0.001) N/A N/A N/A
skin surface on the right clinical test period.
cheek. The texture small
(Ra) values of the right
cheek.
Prakoeswa et 4 weeks and Pore (baseline) NS: 49.63 ± 11.193 Yes N/A Side effect Erythema, urticaria
al18 8 weeks AMSC-CM: 53.17 ± 4.565 (resolved after 2 days
with topical 1%
Pore 4 weeks NS: 49.58 ± 6.903 N/A hydrocortisone cream).
AMSC-CM: 51.42 ± 4.745
Pore 8 weeks NS: 50.29 ± 4.467 N/A

AMSC-CM: 48.46 ± 6.171
Wrinkle (baseline) NS: 12.13 ± 7.011 Yes N/A

AMSC-CM: 13.92 ± 6.639
Wrinkle 4 weeks NS: 12.29 ± 6.196 N/A

AMSC-CM: 12.42 ± 6.413
Wrinkle 8 weeks NS: 11.67 ± 5.498 N/A

AMSC-CM: 9.29 ± 5.279
Spot (polarized) NS: 32.79 ± 8.968 Yes N/A

(baseline) AMSC-CM: 34.96 ± 6.557
Spot (polarized) NS: 34.46 ± 7.852 N/A

4 weeks AMSC-CM: 32.71 ± 7.474
Spot (polarized) NS: 34.08 ± 9.016 N/A

8 weeks AMSC-CM: 30.46 ± 8.335
Spot (UV) baseline NS: 14.54 ± 8.748 Yes N/A
Assessment
outcome
AMSC-CM: 17.17 ± 8.646
Spot (UV) 4 weeks NS: 13.50 ± 5.934 N/A

AMSC-CM: 13.67 ± 5.880
Spot (UV) 8 weeks NS: 13.04 ± 6.196 N/A

AMSC-CM: 12.46 ± 7.581
Skin tone (baseline) NS: 38.58 ± 8.717 No N/A

AMSC-CM: 39.54 ± 7.028
Skin tone 4 weeks NS: 38.58 ± 8.677 N/A

AMSC-CM: 38.96 ± 7.624
Skin tone 8 weeks NS: 36.67 ± 7.750 N/A

AMSC-CM: 36.92 ± 6.788
Kim et al19 2 weeks and Dermal density baseline 14.20 ± 0.09 - N/A Adverse reaction No adverse reaction
4 weeks 2 weeks 14.33 ± 0.08 No
4 weeks 14.55 ± 0.10 Yes
Skin wrinkle
Ra baseline 13.62 ± 0.56 - N/A
Ra 2 weeks 13.40 ± 0.50 No
Ra 4 weeks 13.08 ± 0.45 No
Rmax baseline 94.93 ± 4.31 - N/A

Rmax 2 weeks 92.97 ± 3.34 No
Rmax 4 weeks 90.35 ± 3.44 Yes
Rz baseline 68.87 ± 2.49 - N/A

Rz 2 weeks 67.10 ± 2.08 No
Rz 4 weeks 66.04 ± 2.15 No
Rp baseline 42.66 ± 1.19 - N/A

Rp 2 weeks 41.70 ± 1.20 No
Rp 4 weeks 40.35 ± 1.02 Yes
Rv baseline 57.23 ± 3.43 - N/A

Rv 2 weeks 56.00 ± 2.54 No
Rv 4 weeks 54.59 ± 2.70 No
Assessment
outcome
Yan Xu et al20 15 days Erythema index N/A N/A Control group > N/A N/A
ASC-CM (p<0.01)
Control group > PSC-
CM (p>0.05)
Melanin index N/A N/A Control group >

ASC-CM (p<0.01)
CM (p<0.01)
ASC-CM < PSC-CM
(P<0.01)
Glossymeter index N/A N/A Control group <

ASC-CM (p<0.01)
Control group < PSC-
CM (p<0.01)
TEWAmeter index N/A N/A Control group >

ASC-CM (p<0.05)
CM (p<0.01)
Corneometer index N/A N/A Control group <

ASC-CM (p<0.01)
Control group < PSC-
CM (p<0.01)
Yang Xu et 4 weeks and Collagen amount control: 19.78% ± 2.01% Yes (p<0,05) N/A Immunohisto MMP-1
al21 8 weeks 4 weeks DA-CM: 34.31% ± 3.44% chemistry MMP-3
control: 19.35% ± 2.53%

Collagen amount DA-CM: 49.33% ± 4.78% Yes (p< 0.05) N/A
8 weeks
control: 19.01%± 2.22%
Collagen Type I DA-CM: 23.14%± 2.43% Yes (p <0.05) N/A
4 weeks
control: 22.02% ± 3.41%
Collagen Type I DA-CM: 45.37% ± 3.07% Yes (p< 0.05) N/A
8 weeks
control: 23.31% ± 1.34%
Collagen Type III DA-CM: 45.93% ± 3.50% Yes (p< 0.05) N/A
Assessment
outcome
4 weeks
control: 23.02% ± 2.42%
Collagen Type III DA-CM: 56.94% ± 6.63% Yes (p< 0.05) N/A
8 weeks
N/A
MMP-1 N/A N/A N/A
MMP-3 N/A N/A
El-Domyati et One month Clinical Improvement Yes (p=0.026). Yes (p<0.001) Side effects Erythema
al22 Left side 33.3 ± 8.95 Edema
Right side 60.6 ±9.77 Pigmentary change
Ecchymosis
Score Yes (p= 0.019) Yes (p=0.003) Crusting
Left side
Very good 0 (0%)
Good 0 (0%)
Moderate 7 (70%)
Mild 3 (30%)
Right side
Very good 1 (10%)
Good 7 (70%)
Moderate 2 (20%)
Mild 0 (0%)
Histological evaluation
Collagen fibers
Before Disorganized collagen bundles
with increased intercellular
spaces
Increased and more organized

After collagen bundles with decreased
interfibrillary spaces
Dense elastotic material

Elastic fiber
Before Elastotic material decreased,
fine and well-arranged new
After elastic fibers
Assessment
outcome
Mean epidermal thickness

Left side 47.55 ± 5.52
Before 62.18± 5.69 Yes (p<0.001) No (p=0.78)
After
Right side 48.19±4.36

Before 64.08± 4.30 Yes (p<0.001) No (p=0.41)
After
Lee et al 23
12 weeks Clinical assessment: Adverse event Mild pain and
Overall satisfaction scores Control: 2.72±1.45 N/A Yes (p<0.05) temporary erythema,
hESC-EPC: 3.25±1.26 mild desquamation
Assessment for Control: 1.32±0.62 N/A Yes (p<0.05)

pigmentation hESC-EPC: 1.54±0.57
Assessment for wrinkle Control: 1.49±0.48 N/A Yes (p<0.05)

hESC-EPC: 1.92±0.42
Non-invasive skin
measurement
Pigmentation Control: 143±11.1 Yes (p<0.05)
Baseline hESC-EPC: 138±14.2
Two weeks Control: 136±12.8 No (p= 0.052)

hESC-EPC: 113±12.1 Yes (p<0.05)
Erythema Control: 268±25.1 Yes (p<0.05)

Baseline hESC-EPC: 271±24.2
Two weeks Control: 243±21.1 No (p>0,05)

hESC-EPC: 255±29.8 Yes (p<0,05)
Wrinkle
R2 value Control: 0.52±0.07 Yes (p<0.05)
Baseline hESC-EPC: 0.58±0.1
Two weeks Control: 0.50±0.1 No (p>0.05)
Assessment
outcome
hESC-EPC: 0.46±0.09 Yes (p<0.05)
R3 value Control: 0.38±0.06 Yes (p<0.05)

Baseline hESC-EPC: 0.4±0.1
Two weeks Control: 0.34±0.1 No (p=0.51)

hESC-EPC: 0.31±0.06 Yes (p<0.05)
Amirthalinga 8 days skin moisture N/A Yes (p<0.05) N/A N/A
m et al13 control group 49.6 ± 3.7 - 55.80 ± 1.2
UVB exposed group 54.60 ± 4.7 - 14.5 ± 1.3
Formulation treated 47.8 ± 3.2 - 37.4 ± 2.5
Erythema Index N/A Yes (p<0.05)

control group N/A
UVB exposed group 286.8 ± 12.9 - 366.2 ± 14.4
Formulation treated 265 ± 14.3 - 271.4 ± 15.9
histological N/A
Epidermal thickness
Control 3.06 ± 0.41
UVB-irradiated 14.25 ± 1.19
Formulation treated 10.98 ± 2.05
Dermal thickness
Control 55.18 ± 3.64
UVB-irradiated 99.21 ± 8.73
Formulation treated 76.38 ± 4.60
Epidermal hyperplasia
Control -
UVB-irradiated +++
Formulation treated +
Hyperkeratosis
Control -
UVB-irradiated +++
Formulation treated +
Infiltration of inflammatory
Assessment
outcome
cells in dermis
Control
UVB-irradiated -
Formulation treated +++
++
Kim et al19 Skin irritation degree after N/A N/A
0.5 h 0
24 h 0
48 h 0
3 weeks Skin texture damaged by Control: 3.74% N/A Yes (p<0.05)

external stimuli Application site: 11.94%
2 weeks and Deep skin elasticity Yes (p<0.05) N/A

4 weeks Ur/Ue value
2 weeks 5.97%
4 weeks 9.34%
Wrinkle assessment Yes (p<0.05) N/A

2 weeks 5.01%
4 weeks 6.23%
Dermal density Yes (p<0.05) N/A

2 weeks 6.97%
4 weeks 12.5%
Right after 1
time use and Skin moisture retention Yes (p<0.05) N/A
after 20 effect in artificial cold wind
minutes of environment
artificial cool Right after 1 time use 543.60%
breeze 20 minutes after cool breeze 452.38%
Wang et al 24
12 weeks Melanin index N/A Yes (p<0,001) week 10 Yes Facial N/A
and week 12 p<0.01 week 2 photograph
p<0.001 week 6, 10, Erythema
12 Adverse effect Dryness
Desquamation
Skin color N/A No Yes Burning
p<0.01 Itching
week 10, 12 Stinging
Assessment
outcome
Skin radiance N/A Yes Yes
p<0.05 week 2 p<0.001 week 6, 10,
p<0.01 week 6, 12 12
Skin surface topography N/A Yes No

SEsm AAPE:
p<0.01, week 6
p<0.001, week 10, 12
Control:
p<0.05, week 12
Yes
SEsc N/A AAPE:
p<0.05, week 10
p<0.01, week 12
Control:
p<0.05, week 10
p<0.01, week 12
Sew N/A Yes

N/A AAPE:
p<0.05, week 2, 6
p<0.001, week 10, 12
Control:
p<0.01, week 10, 12
Yes
Value at each time N/A AAPE:
p<0.01, week 2
p<0.001, week 6, 10,
12
Control:
p<0.05, week 10
p<0.01, week 12
Yes
Skin elasticity N/A Yes p<0.05 week 2
R2 value AAPE: p<0.01 week 6
Assessment
outcome
Forehead p<0.001, week 6, 10, p<0.001 week 10, 12
12
Control:
p<0.01, week 10, 12
Yes Yes
AAPE: p<0.01 week 2, 12
p<0.01, week 2 p<0.001 week 6, 10
Crow’s feet p<0.001, week 6, 10,
12
Control:
p<0.05, week 10
p<0.01, week 12
Yes
AAPE:
p<0.05, week 2 Yes
Periorbital skin relief AAPE week 12: p<0.01, week 6,10,12 p<0.05 week 12
Ra -3.08±2.61 Yes
AAPE:
p<0.05, week 2, 10
p<0.01, week 6,12 Yes
p<0.01 week 12
Yes
Rq -3.83±3.15 AAPE:
p<0.05, week 2, 6, 10
p<0.001, week 12
Yes
Yes p<0.01 week 12
AAPE:
Rz -11.48±10.01 p<0.05, week 2, 6, 10
p<0.01, week 12
Yes
p<0.05 week 12
Rmax -21.66±21.90
N/A
Assessment
outcome
N/A
Yes
Self-evaluation p<0.01 week 2, 6,
questionnaire N/A 10, 12
Anti aging
Wrinkles N/A Yes
p<0.05, week 2
N/A p<0.01 week 6, 10,
Wrinkles around eyes N/A 12
Yes
N/A p<0.05, week 2, 6
Skin more resilient N/A p<0.01 week 10, 12
Yes
N/A p<0.05, week 2, 10
Skin more elastic N/A p<0.01 week 6, 12
Yes
p<0.05, week 2, 6
Lifting effect N/A p<0.01 week 10, 12
N/A
Yes
p<0.05, week 2,
Fine wrinkles reduced N/A 10,12
p<0.01 week 10, 6
N/A
Whitening and moisturizing

Feels rejuvenated Yes
N/A N/A p<0.05, week 10
p<0.01, week 6, 12
p<0.001, week 2
Skin more hydrated Yes

N/A N/A p<0.01, week 2, 6,
10
Assessment
outcome
p<0.001, week 12
Skin more radiant
N/A N/A Yes
p<0.05, week 2
p<0.01, week 10
p<0.001, week 6, 12
Skin healthier N/A
N/A Yes
p<0.01, week 2, 6,
10
Skin more fair p<0.001, week 12
N/A
Yes
p<0.01, week 2, 6,
Overall satisfaction 10
N/A p<0.001, week 12
Yes
p<0.05, week 2
p<0.01, week 6, 10
p<0.001, week 12
Kwon et al25 8 weeks TEWL N/A N/A Yes Immunohisto Type I collagen
p<0.001, normal chemistry Epidermal thickening
group, adenosine and Histological Collagen fiber
10% MSC-CM group evaluation
p<0,01, UVB, 1%
MSC-CM
Skin hydration N/A N/A Yes

p<0.001, normal
group
p<0.01, 1% MSC-CM
Keratin content N/A N/A Yes

p<0.001, normal
group, adenosine,1 %
MSC-CM and 10%
MSC-CM group
Wrinkle area N/A N/A Yes
Assessment
outcome
p<0.001, normal
MSC-CM and 10%
MSC-CM group
Clinical score N/A N/A Yes

p<0.001, normal
MSC-CM and 10%
MSC-CM group
Winawati Eka Putri et al / Mesenchymal Stem Cells-Conditioned Medium (SECRETOME) in Skin Aging:
A Systematic Review
Assessment of methodology quality et al was significantly improved between group in

Study characteristics: Table 1 presented an week 2, week 6 and week 1224. Xu et al,
overview of the study, which describes the type of Amirthalingam et al and Kwon et al, used
MSC and CM level used, study design, human or photoaged mice model to observe the effect of
animal model for in vivo study, cell preparation MSC-CM13,19,21. Amirthalingam et al and Kwon et
for in vitro study, and the intervention. Table 2 al, that uses both BMSC-CM, reported an
mostly describes the study’s outcomes. improvement in clinical and histological
Out of 11 studies, 8 were human-model clinical outcomes13,19,21.
studies, and 2 studies mentioned the Fitzpatrick Histological outcomes were reported in 4 studies,
skin type and only 1 mentioned Glogau all of which showed good improvements in the
classification for photoaging. Others did not histological structure of aging skin, and 2 studies
mention the classification. Furthermore, 3 studies showed significance difference from baseline. Xu
in this review used mice, including nude BABL/C et al reported the significant increase of collagen
and, SKH-1 hairless, and nude mice (NU/NU). amount, collagen type I and collagen type III in
The aging model in animal was established by BABL/C mice treated with DA-CM, compared with
irradiating with UVB light. control (DMEM) group for 4 weeks and 8 weeks.
The most common type of MSC used was adipose Domyati et al reported that after one-month
tissue (five studies), followed by bone marrow (two treatment, mean epidermal thickness left side
studies), amnion tissue, epidermal progenitor cell, (microneedle only) and right side (microneedle
human umbilical cord blood, placental tissue and and AF-MSC-CM) increased significantly;
amniotic fluid. Topical MSC was used in 5 studies, however, there is no significance difference
while injection was used in 2. Prakoeswa et al, between these group.
Lee et al, Wang et al and Domyati et al used Other evaluations performed by the authors aim
microneedle and MSC-CM compared between to monitor side effect or adverse reaction, facial
treatment group and the control group. Study photograph and immunohistochemistry. Lee et al
carried out by Xu et al compared between ASC- reported mild pain, temporary erythema and mild
CM or PSC-CM, which was combined with desquamation with microneedle. Similar to Lee et
hyaluronic acid. al, Prakoeswa et al and Domyati et al also used
In vivo study outcomes: Table 2 presented In vivo microneedle and reported erythema. Only Xu et
and clinical study outcomes, including the main al conducted immunohistochemistry examination.
outcomes measures, the scores or results, All results supported the beneficial effects of MSC-
significant difference, and also other outcome CM in the treatment of skin aging.
measures. Out of 11 studies, clinical outcomes
were mostly reported. Sohn et al, Prakoeswa et al, DISCUSSION
Kim et al reported the significant clinical The medium or secretome conditioned by
improvement from baseline, which includes mesenchymal stem cells contains many growth
Crow’s feet, skin surface, skin texture; pore, factors, cytokines, chemokines as well as
wrinkle, spot, skin tone; dermal density, Rmax, extracellular matrix proteins and exosomes. These
Rp; and pore, wrinkle, pigment, moisture, skin secreted factors can play a role in tissue repair
elasticity, sebum U zone, and T zone, and regeneration through their paracrine effect
respectively17–19. Otherwise, Yan Xu et al only 10–12,26,27
. This study showed that MSC-CM is
reported significance difference between the always associated with significantly better clinical
control group and the treatment group20. Index of and histological outcomes. In addition, 11 clinical
Melanin, Glossymeter, Tewameter and or in vivo studies showed improvement of clinical
Corneometer of ASC-CM and PSC-CM group outcomes with or without histological outcomes.
showed improvement than control group for 15 Some studies performed in vitro study to support
days. However, Erythema index, reported in vivo studies.
significance difference from baseline only in ASC- An in vitro study performed by Xu et al, Sohn et
CM group. Melanin index of ASC-CM group was al, and Pan et al, all reported an increase in
significantly lower than PSC-CM group. Lee at al superoxide dismutase (SOD). The combined laser
showed that after treatment for 12 weeks with therapy and ASC-CM conducted by Xu et al also
microneedle and hESC-EPC CM, clinical showed a decrease in malondialdehyde (MDA)
assessment such as overall satisfaction scores, and increased in the expression of Wnt/ β-
assessment for pigmentation and wrinkle were catenin, which plays a role in collagen formation
significantly improved between control and hESC- for the improvement of skin aging21. Sohn et al
EPC CM group. Pigmentation, wrinkle and did culture of HDF with H2O2 and reported that
erythema were significantly decreased in 12 hEPC-CM and MSC-CM have similar protective
weeks. The overall satisfaction reported by Wang effects on SOD and glutathione peroxidase (GPx),
A Systematic Review
which significantly increase type I procollagen studies used different cell sources, research
also inhibited hydrogen peroxide-induced subject, and delivery methods, which clearly leads
phosphorylation of proteins in mitogen activated to different outcomes. The studies used in our
protein kinase (MAPK) signalling and play a role review varies considerably in terms of MSC
in skin aging17. Parado et al28 demonstrated that sources (epidermal progenitor cell, amniotic
AMSC-CM increased catalase (CAT) and membrane, adipose, bone marrow, umbilical
decreased malondialdehyde (MDA) also blocked cord blood, placental, and amniotic fluid),
cell cycle. These could delay oxidative research subjects (human, mice), and delivery
stress‑induced premature senescence 28. Kim et al methods (with or without device-microneedle,
reported that cell migration and collagen type I laser, with or without additional material-
and type III synthesis were increased in the UCB- hyaluronic acid). Finally, the clinical outcomes
MSC CM group than in HDF-CM and ASC-CM. and the device used in measuring the same index
They also reported that GDF11 (rejuvenation also varies between studies. Therefore, it was
factor) secretion was the highest in UCB-MSC impossible to perform a quantitative analysis with
CM, and therefore improving the skin wrinkles19. the included studies. Further research is needed to
GDF-11 or bone morphogenetic protein-11 decide which type of MSC-CM will be the best
(BMP-11), member of TGF-β family, decreases choice for skin aging and to know more about
with age. Although not high, ASC also secretes mechanism of MSC-CM in skin aging
GDF-11, which can improve proliferation, improvement.
differentiation of cell and migration and secretion
of ECM that is important for skin aging29. CONCLUSION
An in vitro study performed by Balasubramanian The use of secretome was promising in improving
et al demonstrated that BMSC-CM showed skin aging process, as shown by the available
beneficial effects on the damaged fibroblasts preclinical studies; however, further clinical
caused by oxidative stress or UV radiation30. The studies are needed to choose which type of MSC
secretome was able to restore fibroblast is superior for the improvements of skin aging.
proliferation and migration, also an increase in
synthesis of ECM26. They also reported an CONFLICT OF INTEREST
increase in the cyclin B1 levels, which decreases There is no conflict of interest in this study
in senescence cell. Another study supported literature.
BMSC-CM as anti-aging, conducted both in vivo
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Mesenchymal Stem Cells-Conditioned Medium (SECRETOME) in Skin Aging:

Article in International Journal for Pharmaceutical Research Scholars · June 2021

Winawati Eka Putri Anang Endaryanto

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INTRODUCTION various types of cells such as adipocytes,

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Fig.1: Prisma Flowchart

Table 1: The studies overview

NHDF cells were pretreated with each

Type of Level Type of

Type of Level Type of

100 mL of adipose tissue was harvested from a

Type of Level Type of

HDF was treated with 2D or 3D cultured

HDF were obtained from males of 20 years old

Type of Level Type of

Table 2: In vivo studies and clinical studies results

Pore 8 weeks NS: 50.29 ± 4.467 N/A

Wrinkle (baseline) NS: 12.13 ± 7.011 Yes N/A

Wrinkle 4 weeks NS: 12.29 ± 6.196 N/A

Wrinkle 8 weeks NS: 11.67 ± 5.498 N/A

Spot (polarized) NS: 32.79 ± 8.968 Yes N/A

Spot (polarized) NS: 34.46 ± 7.852 N/A

Spot (polarized) NS: 34.08 ± 9.016 N/A

Spot (UV) baseline NS: 14.54 ± 8.748 Yes N/A

Spot (UV) 4 weeks NS: 13.50 ± 5.934 N/A

Spot (UV) 8 weeks NS: 13.04 ± 6.196 N/A

Skin tone (baseline) NS: 38.58 ± 8.717 No N/A

Skin tone 4 weeks NS: 38.58 ± 8.677 N/A

Skin tone 8 weeks NS: 36.67 ± 7.750 N/A

Rmax baseline 94.93 ± 4.31 - N/A

Rz baseline 68.87 ± 2.49 - N/A

Rp baseline 42.66 ± 1.19 - N/A

Rv baseline 57.23 ± 3.43 - N/A

Melanin index N/A N/A Control group >

Glossymeter index N/A N/A Control group <

TEWAmeter index N/A N/A Control group >

Corneometer index N/A N/A Control group <

control: 19.35% ± 2.53%

Increased and more organized

Dense elastotic material

Mean epidermal thickness

Right side 48.19±4.36

Assessment for Control: 1.32±0.62 N/A Yes (p<0.05)

Assessment for wrinkle Control: 1.49±0.48 N/A Yes (p<0.05)

Two weeks Control: 136±12.8 No (p= 0.052)

Erythema Control: 268±25.1 Yes (p<0.05)

Two weeks Control: 243±21.1 No (p>0,05)

Two weeks Control: 0.50±0.1 No (p>0.05)

R3 value Control: 0.38±0.06 Yes (p<0.05)