In vitro migration and proliferation (“wound healing”) potential of mesenchymal stromal cells generated from human CD271+ bone marrow mononuclear cells
© Latifi-Pupovci et al. 2015
Received: 7 August 2015
Accepted: 16 September 2015
Published: 25 September 2015
Emerging evidence indicates that mesenchymal stromal cells (MSCs) isolated from different tissue sources may be used in vivo as tissue restorative agents. To date, there is no evidence, however, on migration and proliferation (“wound healing”) potential of different subsets of MSCs. The main goal of this study was therefore to compare the in vitro “wound healing” capacity of MSCs generated from positively selected CD271+ bone marrow mononuclear cells (CD271-MSCs) and MSCs generated by plastic adherence (PA-MSCs).
The in vitro model of wound healing (CytoSelect™ 24-Well Wound Healing Assay) was used in order to compare the migration and proliferation potential of CD271-MSCs and PA-MSCs of passage 2 and 4 cultured in presence or absence of growth factors or cytokines.
CD271-MSCs of both passages when compared to PA-MSCs demonstrated a significantly higher potential to close the wound 12 and 24 h after initiation of the wound healing assay (P < 0.003 and P < 0.002, respectively). Noteworthy, the migration capacity of PA-MSCs of second passage was significantly improved after stimulation with FGF-2 (P < 0.02), PDGF-BB (P < 0.006), MCP-1 (P < 0.002) and IL-6 (P < 0.03), whereas only TGF-β enhanced significantly migration process of PA-MSCs of P4 12 h after the treatment (P < 0.02). Interestingly, treatment of CD271-MSCs of both passages with growth factors or cytokines did not affect their migratory potential.
Our in vitro data provide the first evidence that CD271-MSCs are significantly more potent in “wound healing” than their counterparts PA-MSCs.
Mesenchymal stromal cells (MSCs) are non-hematopoietic multipotent cells which can be derived from bone marrow mononuclear cells , adipose tissue [2, 3] or other tissues such as fetal liver, lungs, spleen [4, 5], amniotic fluid , cord blood , cord [8, 9], placenta [10, 11], endometrium  and dental pulp . MSCs can be generated either by plastic adherence of progenitor cells for MSCs (PA-MSCs) or by a positive selection with antibodies against cell surface antigens expressed by MSC-progenitor cells (D7-FIB, CD271, SSEA-4, GD2 and frizzled-9) [14–18]. CD271 (Low-affinity nerve growth factor receptor) antigen is present on human bone marrow cells and potentially defines a mesenchymal stromal cell (MSC) precursor subpopulation. Abundant evidence suggest that MSCs, isolated from different tissue sources, confer benefits in vivo as tissue restorative agents . Wound healing is a complex process that requires the coordinated interplay of extra cellular matrix, growth factors, and cells. The presence of MSCs in normal skin and their critical role in wound healing suggests that the application of exogenous MSCs is a promising strategy to treat non-healing wounds resulting from trauma, diabetes, vascular insufficiency, and numerous other conditions . Bone marrow-derived mesenchymal stem cells (BM-MSCs) promote the healing of diabetic wounds due to increased re-epithelialization, cellularity, and angiogenesis [21, 22]. These cells may participate directly in wound closure through progenitor cell proliferation and differentiation, as well as production of extracellular matrix (ECM) . Several studies have shown that BM-MSCs secrete a variety of cytokines and growth factors which are known to enhance normal wound healing [24–27] including fibroblast growth factor-2 (FGF-2), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), transforming growth factor beta (TGF-β) [28, 29], hepatocyte growth factor (HGF), interleukin 6 (IL-6), interleukin 8 (IL-8)  vascular endothelial growth factor (VEGF), stromal cell-derived factor (SDF)  and insulin-like growth factor-1 (IGF-1) [30–32]. Despite several in vivo studies which demonstrated the impact of MSCs on wound healing [33, 34], there is so far no evidence on wound healing potential of different subsets of mesenchymal stromal cells. In this in vitro study we focused on migration and proliferation (“wound healing”) capacity of MSCs generated from CD271+ bone marrow mononuclear cells (CD271-MSCs) and compared it to MSCs generated by plastic adherence (PA-MSCs). In addition, we evaluated the effect of different growth factors and cytokines in migration and proliferation potential of these cells.
Isolation of bone marrow mononuclear cells (BM-MNCs)
Bone marrow aspirates were taken from the iliac crest of 4 male healthy donors (age: 18–22 years) after informed consent and under a protocol approved by the University of Frankfurt Institutional Review Board. After dilution 1:2 in PBS, aspirates were centrifuged in 1.073 g/ml Ficoll density gradient in 700×g for 30 min. The enriched cells were collected from the interface, washed twice with PBS (PAA Laboratories GmbH, Austria) and centrifuged at 400×g for 10 min. A defined number of isolated BM-MNCs were used for generation of PA-MSCs whereas the majority of them were used for enrichment of CD271+ cells.
Generation of CD271-MSCs
CD271+ bone marrow mononuclear cells were isolated immune-magnetically using the MSC Research Tool Box–CD271 (LNGFR)-APC (Miltenyi Biotec GmbH), according to the manufacturer’s instructions. Highly purified bone marrow CD271+ mononuclear cells (1.25 × 105/cm2) were seeded in T25 (25 cm2) culture flasks with vent caps in 6 ml DMEM low-glucose supplemented with 10 % MSC-qualified fetal bovine serum (FBS) (GIBCO/Invitrogen, Darmstadt). The medium was changed after 7 days and later on every third day until the cells reached the confluence 70–80 % (10–14 day). MSCs generated in this way are referred to as CD271-MSCs throughout the manuscript. After this step the whole procedure was the same as for generation of PA-MSCs.
Generation of PA-MSCs
To generate PA-MSCs, BM-MNCs were cultured in DMEM low-glucose supplemented with 10 % MSC-qualified FBS. The cells were maintained at 37 °C in 95 % humidified atmosphere of 5 % CO2 for 72 h. Thereafter, the nonadherent cells were removed and fresh medium was added and changed every 2 or 3 days. The adherent spindle-shaped cells were further cultured for 10–14 days until the cells reached about 70–80 % confluence. During this time the medium was changed every 3 days. To detach the MSCs the medium was removed and the cells were washed once with PBS. The cells were detached by exposure to trypsin TrypLE (Invitrogen) for 6 min at 37 °C, followed by tapping the dishes and the addition of culture medium. The cells were centrifuged then resuspended with medium and plated at a density of 2 × 103 MSCs/cm2. During culture the medium was changed every 3 days, and when the cells were confluent they were passaged. The cells were passaged three times, and cells from the second and fourth passage were used for experiment.
Colony forming unit-fibroblast assay and expansion potential of CD271-MSCs
To assess the clonogenic potential of positively selected CD271+ cells and BM-MNC, the CFU-F assay was performed in 25 cm2 tissue culture flasks. For this purpose, 2.5 × 105 BM-MNC/25 cm2, and 2.5 × 104 cells/25 cm2 from the CD271-positive fraction were cultured for 14 days. Colonies were stained with Giemsa solution (Merck, Darmstadt, Germany) and counted.
Immunophenotyping of CD271-MSCs and PA-MSCs
CD271-MSC and PA-MSC of different passages (from passage 1 to passage 4) were stained with fluorochrome-conjugated mouse anti-human antibodies against following antigens CD73, CD90, CD105, CD146, CD44, CD29, CD166, CD45, CD34 and CD14 and HLA-Class I and HLA Class II molecules and incubated at 4 °C for 30 min. After two wash steps with PBS + 0.2 % BSA the stained cells were analyzed on a FACSCalibur (Becton–Dickinson) equipped with Macintosh software for data analysis (CellQuest).
Trilineage differentiation of MSCs
To induce differentiation of MSCs, specific medium was added to the cells according to the manufacturer’s instructions. Adipogenic differentiation was induced by NH Adipo Diff Medium (Miltenyi Biotec, Bergisch Gladbach). Osteogenic differentiation was achieved by NH OsteoDiff Medium (Miltenyi Biotec, Bergisch Gladbach), whereas chondrogenic differentiation was induced by NH ChondroDiff Medium (Miltenyi Biotec, Bergisch Gladbach). Each specific differentiation medium was changed every 2–3 days. Confirmation of differentiation of the cells to adipocytes, osteocytes and chondrocytes were performed by staining with Oil Red O staining solution, SIGMA FAST™ BCIP/NBT (5-bromo-4-chloro-3-indolyl phosphate/nitro blue tetrazolium) tablets and Alcian blue-solution, respectively.
Wound healing assay
The wound healing process entails the migration and proliferation of different cells, including the MSCs. To compare the wound healing potential of CD271-MSCs and PA-MSCs, the second and fourth passage MSCs were cultured in DMEM containing 1 % FBS. To analyze the wound healing capacity, we used an in vitro model of wound healing (CytoSelect™ 24-Well Wound Healing Assay) from the Cell Biolabs company (BIOCAT GmbH, Heidelberg, Germany). The CytoSelect™ 24-well Wound Healing Assay Kit consists of 2 × 24-well plates each containing 12 proprietary treated plastic inserts. The inserts create a wound field with a defined gap of 0.9 mm for measuring the migration and proliferation rate of cells. In order to precisely find the same position at making the photographs, the center of each well was labeled before adding the cells.
Growth factors and cytokines assessed for their effect on wound healing potential of MSCs
Growth factors and cytokines
Pepro Tech [GmbH-Hamburg, Germany]
Human MCP-1 [MCAF]
Rabbit anti-human PDGF-basic
Effect of some growth factors and cytokines in “wound healing” capacity of MSCs
To assess how different growth factors and cytokines affect migration capacity we compared the effects of following 10 growth factors/cytokines on migratory activity of CD271-MSCs and PA-MSCs: epidermal growth factor (EGF), transforming growth factor beta (TGFβ), hepatocyte growth factor (HGF), fibroblast growth factor 2 (FGF-2), stromal-derived growth factor-1α (SDF-1α), monocyte chemotactic protein-1 (MCP-1), interleukin 8 (IL-8), interleukin 6 (IL-6) and platelet-derived growth factor BB (PDGF-BB). To get additional insights into possible mechanisms involved in the migratory potential of MSCs we used antibodies against one of the key players in this process, platelet-derived growth factor BB (Ab-PDGF- BB) (Table 1).
Data were analyzed by using standard statistical software (GraphPad Prism Software, San Diego, CA, USA). Results are expressed as mean value ± standard deviation. The statistical significance of values between two groups was evaluated by Student’s t test. Differences were considered significant when the P-value was 0.05 or less.
Results and discussion
Phenotype and trilineage differentiation potential of CD271-MSCs and PA-MSCs
Evaluation of “wound closure” potential of MSCs
MSCs of both types were cultured 24 h until a monolayer formed at which time the inserts were removed to begin the wound healing assay. Cells were monitored under phase contrast (not shown) and followed by cell staining for determination of percent closure (0, 50, 75, and 100 %).
The effect of passages on the “wound healing” potential of MSCs
CD271-MSCs possess a higher “wound healing” potential than PA-MSCs
In the current study we assessed the “wound healing” potential of CD271-MSCs and PA-MSCs both in the absence (DMEM supplemented with 1 % FCS only: control) and presence of GFs/Cytokines.
When compared “wound healing” capacity of CD271-MSCs to PA-MSCs in the absence (DMEM supplemented with 1 % FCS) of GFs/Cytokines, CD271-MSCs of passage 2 demonstrated a significantly higher potential to close the wound 12 and 24 h after initiation of the wound healing assay (P < 0.003 and P < 0.002, respectively). No differences were observed in the first 6 h of the wound closure (Fig. 3c). However, the “wound healing” potential of CD271-MSCs of passage 4 was significantly higher compared to PA-MSCs of the same passage only 12 h after initiation of the assay (P < 0.03) and no difference was observed for the time-points 6 and 24 h (Fig. 3d). Therefore, these data indicate that in particular CD271-MSCs of passage 2 are superior to PA-MSCs in the first 12 h of the healing process, demonstrating for the first time that these MSCs possess a higher migratory potential than PA-MSCs.
Effect of various growth factors and cytokines on in vitro migration and proliferation potential of MSCs at different passages
In contrast, neither growth factors nor cytokines were able to improve migration capacity of the second passage CD271-MSCs. Similarly to second passage, migration capacity and healing potential of passage 4 CD271-MSCs was not affected by a 12 h treatment with growth factors or cytokines (Fig. 4d). The greater capacity of CD271-MSCs to produce higher levels of cytokines than PA-MSCs  may account for this non-responsiveness of these cells to exogenously added cytokines/growth factors.
To the best of our knowledge, we show for the first time that during the wound closure, both CD271-MSCs and PA-MSCs of passage 4 were superior to MSCs of passage 2. In addition, the CD271-MSCs demonstrated a significantly higher “wound healing” potential than PA-MSCs, suggesting that they may be more effective in the treatment of the wounds.
HL-P and ZK were involved in experimental design, execution of experiments and writing of manuscript, whereas SW and RL contributed in preparation and staining of adipocytes, osteoblasts and chondrocytes. HB, TK, PB and SK were involved in experimental design and writing of the manuscript. All authors read and approved the final manuscript.
The authors would like to thank the Robert Pfleger Stiftung, DKMS and Else Kröner-Fresenius-Stiftung (2011_A186) for funding this study. The authors also express their gratitude to Frankfurter Stiftung für krebskranke Kinder (Frankfurt, Germany) for the kind financial support of SK.
Compliance with ethical guidelines
Competing interests The authors declare that they have no competing interests.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
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