Special Issue "Research on Adipose Stem Cells"

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Stem Cells".

Deadline for manuscript submissions: 1 July 2021.

Special Issue Editor

Prof. Dr. Bruce A. Bunnell
E-Mail Website
Guest Editor
University of North Texas Health Science Center
Interests: mesenchymal stem cells; adipose; regeneration; SVF, exosomes, therapy; tissue engineering

Special Issue Information

Dear Colleagues,

Stem cell therapies have shown potential benefits in a variety of human diseases. Adipose tissue is a rich source of cells with regenerative potential. Adipose-tissue‐derived cell products, including the stromal vascular fraction (SVF) and stromal/stem cells (ASC), possess the capacity for homing, immunomodulation, promotion of repair, and direct regeneration of damaged tissues, which make them promising therapeutic interventions for numerous diseases. ASCs also produce soluble factors and extravascular vesicles (exosomes and microvesicles) that have been demonstrated to have therapeutic effects. The cargo contained within microvesicles is a complex mix of proteins, lipids, DNA, mRNAs, microRNAs, tRNA, and non-coding RNAs that are delivered to other cells and can have biological impacts. SVF, ASC, and ASC-derived microvesicles are promising candidates as cellular therapies due to their abundance, ease of isolation, and natural mechanisms for mediating tissue regeneration. Pre-clinical and clinical studies indicate that each of them have the potential to improve disease outcomes.

This Special Issue focused on Adipose Stem Cells seeks original research and review articles with a focus on:

  1. Biological characterization of cell populations with regeneration potential isolated from adipose tissue: SVF and ASCs;
  2. Biological characterization and therapeutic application of microvesicles produced by ASCs;
  3. Studies on mechanisms of action of cells and microvesicles;
  4. Therapeutic applications in pre-clinical models and clinical trials.

Prof. Dr. Bruce A. Bunnell
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2000 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Adipose stem cells (ASCs)
  • Stromal vascular fraction (SVF)
  • Microvesicles
  • Basic biology
  • Mechanisms of action
  • Therapeutics

Published Papers (10 papers)

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Research

Open AccessArticle
Beiging Modulates Inflammatory Adipogenesis in Salt-Treated and MEK6–Transfected Adipocytes
Cells 2021, 10(5), 1106; https://doi.org/10.3390/cells10051106 - 04 May 2021
Viewed by 339
Abstract
To investigate whether the beiging process changes the interactive effects of salt and MEK6 gene on inflammatory adipogenesis, the salt treatment (NaCl 50 mM) and MEK6 transfection of Tg(+/+) cells were performed with white adipocytes (WAT) and beige-like-adipocytes (BLA). BLA induced by [...] Read more.
To investigate whether the beiging process changes the interactive effects of salt and MEK6 gene on inflammatory adipogenesis, the salt treatment (NaCl 50 mM) and MEK6 transfection of Tg(+/+) cells were performed with white adipocytes (WAT) and beige-like-adipocytes (BLA). BLA induced by T3 were confirmed by UCP-1 expression and the MEK6 protein was 3.5 times higher in MEK6 transfected WAT than the control. The adipogenic genes, PPAR-γ and C/EBP-α, were 1.5 times more highly expressed in the salt-treated groups than the non-salt-treated groups, and adipogenesis was greatly increased in Tg(+/+) WAT compared to non-transfected Tg(−/−). The adipogenesis induced by salt treatment and MEK6 transfection was significantly reduced in BLA. The inflammatory adipocytokines, TNF-α, IL-1β, and IL-6, were increased in the salt-treated Tg(+/+) WAT, but an anti-inflammation biomarker, the adiponectin/leptin ratio, was reduced in Tg(+/+), to tenth of that in Tg(−/−). However, the production of adipocytokines in WAT was strongly weakened in BLA, although a combination of salt and MEK6 transfection had the most significant effects on inflammation in both WAT and BLA. Oxygen consumption in mitochondria was maximized in salt-treated and MEK6 transfected WAT, but it was decreased by 50% in BLA. In conclusion, beiging controls the synergistic effects of salt and MEK6 on adipogenesis, inflammation, and energy expenditure. Full article
(This article belongs to the Special Issue Research on Adipose Stem Cells)
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Open AccessArticle
Facial Rejuvenation with Concentrated Lipograft—A 12 Month Follow-Up Study
Cells 2021, 10(3), 594; https://doi.org/10.3390/cells10030594 - 08 Mar 2021
Viewed by 368
Abstract
Lipofilling is a popular technique to treat volume loss in aging patients. The isolated adipose tissue is composed of adipocytes and stromal vascular fraction cells, which include adipose-derived stem cells (ASC). We hypothesize that the patient’s wrinkle severity scale (WSS) and patient’s satisfaction [...] Read more.
Lipofilling is a popular technique to treat volume loss in aging patients. The isolated adipose tissue is composed of adipocytes and stromal vascular fraction cells, which include adipose-derived stem cells (ASC). We hypothesize that the patient’s wrinkle severity scale (WSS) and patient’s satisfaction on the global aesthetic improvement scale (GAIS) can be improved after using concentrated lipoaspirate. Fourteen patients (54 years ± 11.09 years) with volume loss in the midface area underwent waterjet-assisted liposuction (Human Med AG, Schwerin, Germany). Fat was centrifuged in an ACP Double Syringe (Arthrex GmbH, Munich, Germany) using Rotofix 32A centrifuge (Andreas Hettich, GmbH & Co.KG, Tuttlingen, Germany). Homogenization was performed using the double syringe and a 1.4 mm female–female luerlock connector. After a second centrifugation, patients received periorbital (PO) and nasolabial (NL) lipografting. ASC count was performed after enzymatical digestion. Vitality of cells was assessed using a resazurin assay. During long-term follow up (12 months, n = 10), we found a high patient’s satisfaction (GAIS 1+/−0.52) and a good improvement of the WSS during short- and long-term follow-up. The ASC count of processed lipoaspirate was 2.1-fold higher than of unprocessed lipoaspirate (p < 0.001). The difference of ASC in sedimented and simply centrifuged lipoaspirate was also significant (p < 0.05). Facial rejuvenation with concentrated fat graft offers good results concerning objective aesthetic outcome and patient’s satisfaction. Full article
(This article belongs to the Special Issue Research on Adipose Stem Cells)
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Open AccessArticle
Selective Proliferation of Highly Functional Adipose-Derived Stem Cells in Microgravity Culture with Stirred Microspheres
Cells 2021, 10(3), 560; https://doi.org/10.3390/cells10030560 - 04 Mar 2021
Viewed by 469
Abstract
Therapeutic effects of adult stem-cell transplantations are limited by poor cell-retention in target organs, and a reduced potential for optimal cell differentiation compared to embryonic stem cells. However, contemporary studies have indicated heterogeneity within adult stem-cell pools, and a novel culturing technique may [...] Read more.
Therapeutic effects of adult stem-cell transplantations are limited by poor cell-retention in target organs, and a reduced potential for optimal cell differentiation compared to embryonic stem cells. However, contemporary studies have indicated heterogeneity within adult stem-cell pools, and a novel culturing technique may address these limitations by selecting those for cell proliferation which are highly functional. Here, we report the preservation of stemness in human adipose-derived stem cells (hASCs) by using microgravity conditions combined with microspheres in a stirred suspension. The cells were bound to microspheres (100−300 μm) and cultured using a wave-stirring shaker. One-week cultures using polystyrene and collagen microspheres increased the proportions of SSEA-3(+) hASCs 4.4- and 4.3-fold (2.7- and 2.9-fold increases in their numbers), respectively, compared to normal culture conditions. These cultured hASCs expressed higher levels of pluripotent markers (OCT4, SOX2, NANOG, MYC, and KLF), and had improved abilities for proliferation, colony formation, network formation, and multiple-mesenchymal differentiation. We believe that this novel culturing method may further enhance regenerative therapies using hASCs. Full article
(This article belongs to the Special Issue Research on Adipose Stem Cells)
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Open AccessArticle
Based on a Self-Feeder Layer, a Novel 3D Culture Model of Human ADSCs Facilitates Trans-Differentiation of the Spheroid Cells into Neural Progenitor-Like Cells Using siEID3 with a Laminin/Poly-d-lysine Matrix
Cells 2021, 10(3), 493; https://doi.org/10.3390/cells10030493 - 25 Feb 2021
Cited by 1 | Viewed by 391
Abstract
Human adipose-derived stromal cells (ADSCs) are receiving unprecedented attention as a potential cellular source for regenerative medicine-based therapies against various diseases and conditions. However, there still have significant issues concerning the translational development of ADSC-based therapies, such as its heterogeneity and being prone [...] Read more.
Human adipose-derived stromal cells (ADSCs) are receiving unprecedented attention as a potential cellular source for regenerative medicine-based therapies against various diseases and conditions. However, there still have significant issues concerning the translational development of ADSC-based therapies, such as its heterogeneity and being prone to aging. We developed a new simple and economical 3D semi-suspended expansion method in which 3D spheroids reside on an ADSC-derived self-feeder cell layer, producing cells with increased population homogeneity and strong stemness and ensuring that the proliferation and differentiation potency of the cells does not become notably reduced after at least ten passages in culture. To check the potential application of the 3D ADSC spheroids, we discovered that the combination of siEID3, which is a small interfering RNA of EP300 inhibitor of differentiation 3 (EID3), and laminin/poly-d-lysine matrix can rapidly result in trans-differentiation of the 3D spheroid cells to neural progenitor-like cells (NPLCs) in approximately 9 days in vitro. This approach provides a multidisciplinary tool for stem cell research and production in mesenchymal stem cell-related fields. Full article
(This article belongs to the Special Issue Research on Adipose Stem Cells)
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Open AccessArticle
Quiescence, Stemness and Adipogenic Differentiation Capacity in Human DLK1/CD34+/CD24+ Adipose Stem/Progenitor Cells
Cells 2021, 10(2), 214; https://doi.org/10.3390/cells10020214 - 22 Jan 2021
Cited by 1 | Viewed by 866
Abstract
We explore the status of quiescence, stemness and adipogenic differentiation capacity in adipose stem/progenitor cells (ASCs) ex vivo, immediately after isolation from human subcutaneous white adipose tissue, by sorting the stromal vascular fraction into cell-surface DLK1+/CD34, DLK1+/CD34 [...] Read more.
We explore the status of quiescence, stemness and adipogenic differentiation capacity in adipose stem/progenitor cells (ASCs) ex vivo, immediately after isolation from human subcutaneous white adipose tissue, by sorting the stromal vascular fraction into cell-surface DLK1+/CD34, DLK1+/CD34dim and DLK1/CD34+ cells. We demonstrate that DLK1/CD34+ cells, the only population exhibiting proliferative and adipogenic capacity, express ex vivo the bonafide quiescence markers p21Cip1, p27Kip1 and p57Kip2 but neither proliferation markers nor the senescence marker p16Ink4a. The pluripotency markers NANOG, SOX2 and OCT4 are barely detectable in ex vivo ASCs while the somatic stemness factors, c-MYC and KLF4 and the early adipogenic factor C/EBPβ are highly expressed. Further sorting of ASCs into DLK1/CD34+/CD24 and DLK1/CD34+/CD24+ fractions shows that KLF4 and c-MYC are higher expressed in DLK1/CD34+/CD24+ cells correlating with higher colony formation capacity and considerably lower adipogenic activity. Proliferation capacity is similar in both populations. Next, we show that ASCs routinely isolated by plastic-adherence are DLK1/CD34+/CD24+. Intriguingly, CD24 knock-down in these cells reduces proliferation and adipogenesis. In conclusion, DLK1/CD34+ ASCs in human sWAT exist in a quiescent state, express high levels of somatic stemness factors and the early adipogenic transcription factor C/EBPβ but senescence and pluripotency markers are barely detectable. Moreover, our data indicate that CD24 is necessary for adequate ASC proliferation and adipogenesis and that stemness is higher and adipogenic capacity lower in DLK1/CD34+/CD24+ relative to DLK1/CD34+/CD24 subpopulations. Full article
(This article belongs to the Special Issue Research on Adipose Stem Cells)
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Open AccessArticle
Simple and Rapid Non-Enzymatic Procedure Allows the Isolation of Structurally Preserved Connective Tissue Micro-Fragments Enriched with SVF
Cells 2021, 10(1), 36; https://doi.org/10.3390/cells10010036 - 29 Dec 2020
Viewed by 580
Abstract
The stromal vascular fraction (SVF) consists of a heterogeneous population of stem and stromal cells, generally obtained from adipose tissue by enzymatic digestion. For human cell-based therapies, mechanical process methods to obtain SVF represent an advantageous approach because they have fewer regulatory restrictions [...] Read more.
The stromal vascular fraction (SVF) consists of a heterogeneous population of stem and stromal cells, generally obtained from adipose tissue by enzymatic digestion. For human cell-based therapies, mechanical process methods to obtain SVF represent an advantageous approach because they have fewer regulatory restrictions for their clinical use. The aim of this study was to characterize a novel commercial system for obtaining SVF from adipose tissue by a mechanical approach without substantial manipulations. Lipoaspirate samples collected from 27 informed patients were processed by a simple and fast mechanical system (by means of Hy-Tissue SVF). The Hy-Tissue SVF product contained a free cell fraction and micro-fragments of stromal connective tissue. The enzymatic digestion of the micro-fragments increased the yield of free cells (3.2 times) and CFU-F (2.4 times). Additionally, 10% of free cells from SVF were positive for CD34+, suggesting the presence of endothelial cells, pericytes, and potential adipose-derived stem cells (ADSC). Moreover, the SVF cells were able to proliferate and differentiate in vitro toward adipocytes, osteocytes, and chondrocytes. The immunophenotypic analysis of expanded cells showed positivity for typical mesenchymal stem cell markers. The Hy-Tissue SVF system allows the isolation of stromal vascular fraction, making this product of potential interest in regenerative medicine. Full article
(This article belongs to the Special Issue Research on Adipose Stem Cells)
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Open AccessArticle
Adipose-Derived Stem Cells from Obese Donors Polarize Macrophages and Microglia toward a Pro-Inflammatory Phenotype
Cells 2021, 10(1), 26; https://doi.org/10.3390/cells10010026 - 25 Dec 2020
Viewed by 905
Abstract
Macrophages and microglia represent the primary phagocytes and first line of defense in the peripheral and central immune systems. They activate and polarize into a spectrum of pro- and anti-inflammatory phenotypes in response to various stimuli. This activation is tightly regulated to balance [...] Read more.
Macrophages and microglia represent the primary phagocytes and first line of defense in the peripheral and central immune systems. They activate and polarize into a spectrum of pro- and anti-inflammatory phenotypes in response to various stimuli. This activation is tightly regulated to balance the appropriate immune response with tissue repair and homeostasis. Disruption of this balance results in inflammatory disease states and tissue damage. Adipose stem cells (ASCs) have great therapeutic potential because of the potent immunomodulatory capabilities which induce the polarization of microglia and macrophages to the anti-inflammatory, M2, phenotype. In this study, we examined the effects of donor heterogeneity on ASC function. Specifically, we investigated the impact of donor obesity on ASC stemness and immunomodulatory abilities. Our findings revealed that ASCs from obese donors (ObASCs) exhibited reduced stem cell characteristics when compared to ASCs from lean donors (LnASCs). We also found that ObASCs promote a pro-inflammatory phenotype in murine macrophage and microglial cells, as indicated by the upregulated expression of pro-inflammatory genes, increased nitric oxide pathway activity, and impaired phagocytosis and migration. These findings highlight the importance of considering individual donor characteristics such as obesity when selecting donors and cells for use in ASC therapeutic applications and regenerative medicine. Full article
(This article belongs to the Special Issue Research on Adipose Stem Cells)
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Open AccessArticle
Safety and Tolerability of Stromal Vascular Fraction Combined with β-Tricalcium Phosphate in Posterior Lumbar Interbody Fusion: Phase I Clinical Trial
Cells 2020, 9(10), 2250; https://doi.org/10.3390/cells9102250 - 08 Oct 2020
Viewed by 774
Abstract
The rates of pseudarthrosis remain high despite recent advances in bone graft substitutes for spinal fusion surgery. The aim of this single center, non-randomized, open-label clinical trial was to determine the feasibility of combined use of stromal vascular fraction (SVF) and β-tricalcium phosphate [...] Read more.
The rates of pseudarthrosis remain high despite recent advances in bone graft substitutes for spinal fusion surgery. The aim of this single center, non-randomized, open-label clinical trial was to determine the feasibility of combined use of stromal vascular fraction (SVF) and β-tricalcium phosphate (β-TCP) for patients who require posterior lumbar interbody fusion (PLIF) and pedicle screw fixation. Two polyetheretherketone (PEEK) cages were inserted into the intervertebral space following complete removal of the intervertebral disc. The PEEK cage (SVF group) on the right side of the patient was filled with β-TCP in combination with SVF, and the cage on the left side (control group) was filled with β-TCP alone. Fusion rate and cage subsidence were assessed by lumbar spine X-ray and CT at 6 and 12 months postoperatively. At the 6-month follow-up, 54.5% of the SVF group (right-sided cages) and 18.2% of the control group (left-sided cages) had radiologic evidence of bone fusion (p = 0.151). The 12-month fusion rate of the right-sided cages was 100%, while that of the left-sided cages was 91.6% (p = 0.755). Cage subsidence was not observed. Perioperative combined use of SVF with β-TCP is feasible and safe in patients who require spinal fusion surgery, and it has the potential to increase the early bone fusion rate following spinal fusion surgery. Full article
(This article belongs to the Special Issue Research on Adipose Stem Cells)
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Open AccessArticle
Development and Validation of a Fully GMP-Compliant Process for Manufacturing Stromal Vascular Fraction: A Cost-Effective Alternative to Automated Methods
Cells 2020, 9(10), 2158; https://doi.org/10.3390/cells9102158 - 24 Sep 2020
Viewed by 692
Abstract
The therapeutic use of adipose-derived stromal vascular fraction (SVF) is expanding in multiple pathologies. Various processes have been proposed for manufacturing SVF but they must be revisited based on advanced therapy medicinal product (ATMP) regulations. We report here the development and validation of [...] Read more.
The therapeutic use of adipose-derived stromal vascular fraction (SVF) is expanding in multiple pathologies. Various processes have been proposed for manufacturing SVF but they must be revisited based on advanced therapy medicinal product (ATMP) regulations. We report here the development and validation of a fully good manufacturing practices (GMP)-compliant protocol for the isolation of SVF. Adipose tissue was collected from healthy volunteers undergoing lipoaspiration. The optimal conditions of collagenase digestion and washing were determined based on measurements of SVF cell viability, yield recovery, and cell subset distribution. Comparability of the SVF obtained using the newly developed manufacturing process (n = 6) and the Celution-based automated method (n = 33), used as a reference, was established using inter-donor analyses. Characteristics of SVF (n = 5) generated using both manufacturing protocols were analyzed for an intra-donor comparison. In addition, these comparisons also included the determination of colony-forming unit fibroblast frequency, in vitro angiogenic activity, and in vivo regenerative effects in a mouse ischemic cutaneous wound model. We successfully developed a process for the generation of SVF presenting higher cell viability and yield recovery compared to the Celution device-based protocol. Characteristics of the SVF including phenotype, capacity for angiogenesis, and wound-healing promotion attested to the comparability of the two manufacturing processes. We validated an optimized non-automated process that should allow for a GMP-compliant, more affordable, and reduced-cost strategy to exploit the potential of SVF-based regenerative therapies. Full article
(This article belongs to the Special Issue Research on Adipose Stem Cells)
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Open AccessArticle
Treatment of Grade 3 and 4 Osteoarthritis with Intraoperatively Separated Adipose Tissue-Derived Stromal Vascular Fraction: A Comparative Case Series
Cells 2020, 9(9), 2096; https://doi.org/10.3390/cells9092096 - 14 Sep 2020
Cited by 1 | Viewed by 828
Abstract
Osteoarthritis (OA) is the most common form of arthritis of the joints. The stromal vascular fraction (SVF) is a regenerative cell population that can be isolated from adipose tissue. It is the immunomodulatory properties of the stromal vascular fraction that make it a [...] Read more.
Osteoarthritis (OA) is the most common form of arthritis of the joints. The stromal vascular fraction (SVF) is a regenerative cell population that can be isolated from adipose tissue. It is the immunomodulatory properties of the stromal vascular fraction that make it a promising candidate for the regenerative treatment of OA. Patients with grade 3 and 4 osteoarthritis were treated with the stromal vascular fraction with and without platelet-rich plasma (PRP) and followed up on their Knee Injury and Osteoarthritis Outcome Score (KOOS) score for 12 months, with MRI and subjective evaluation of the procedure. Magnetic resonance imaging (MRI) revealed a widening of the joint space, a restructuring of the cartilage, and an alleviation of effusions in the treated joints. In three of the four treatment groups, a substantial improvement of the KOOS scores was documented at the 12-month follow-up time point. According to the subjective evaluation, 67% of the patients were satisfied or very satisfied with the procedure and would recommend it to others. No serious adverse events or unwanted side effects related to the SVF treatment were observed or reported. Prior to an invasive artificial joint replacement, the treatment of arthritic knee joints with the intraarticular injection of autologous adipose tissue-derived SVF should be considered a regenerative treatment option. Full article
(This article belongs to the Special Issue Research on Adipose Stem Cells)
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