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Review
. 2022 Mar;18(3):952-967.
doi: 10.1007/s12015-021-10252-5. Epub 2021 Sep 12.

Application of ADSCs and their Exosomes in Scar Prevention

Cong Li  1 , Shuqiang Wei  2 , Quanchen Xu  1 , Yu Sun  1 , Xuchao Ning  1 , Zhiguo Wang  3
Affiliations
Review

Application of ADSCs and their Exosomes in Scar Prevention

Cong Li et al. Stem Cell Rev Rep. 2022 Mar.

Abstract

Scar is a common way of healing after tissue injury. The poor scar healing will not only cause dysfunction of tissues and organs but also affect the appearance of the patients' body surface, which causes the pressure of life and spirit to the patients. However, the formation of scar tissue is an extremely complex process and its mechanism is not fully understood. At present, there is no treatment method to eliminate scars completely. Fibroblasts are the most abundant cells in the dermis, which have the ability to synthesize and remodel extracellular matrix (ECM). Myofibroblasts actively participate in the wound healing process and influence the outcome. Therefore, both of them play important roles in wound healing and scar formation. Adipose tissue-derived stem cells (ADSCs) are pluripotent stem cells that can act on target cells by paracrine. Adipose tissue stem cell-derived exosomes (ADSC-Exos) are important secretory substances of ADSCs. They are nanomembrane vesicles that can transport a variety of cellular components and fuse with target cells. In this review, we will discuss the effects of ADSCs and ADSC-Exos on the behavior of fibroblasts and myofibroblasts during wound healing and scarring stage in combination with recent studies.

Keywords: Adipose tissue-derived stem cells; Exosomes; Fibroblasts; Myofibroblasts; Scar; Wound healing.

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Conflict of interest statement

The authors have no conflicts of interest to declare.

Figures

Fig. 1
Fig. 1
The role of fibroblasts and myofibroblasts in scar formation. (1) During the inflammatory phase, various cytokines and inflammatory factors stimulate fibroblasts to undergo phenotypic changes. (2) In the proliferative phase, fibroblasts produce large amounts of cytokines and extracellular components by secretory action, which cause ECM accumulation. Fibroblasts are transformed into myofibroblasts through differentiation, which cause wound contraction and further ECM accumulation. Meanwhile, the migratory of fibroblasts is enhanced. (3) During the remodeling phase, the extracellular component secreted by fibroblasts is reduced and the MMPs secreted by fibroblasts help the scar remodeling. Concurrently, fibroblasts and myofibroblasts are partially apoptotic, which contributed to the reduction of ECM. (4) EMT also has an important role in wound healing, during which epidermal cells and endothelial cells can differentiate into fibroblasts and myofibroblasts. “↑” and “↓” represent increase and decrease, respectively
Fig. 2
Fig. 2
The extraction and differentiation of ADSCs. Adipose tissue should be collected from patients with no underlying disease, adverse lifestyle preferences, or a history of drugs that affect fat metabolism. 25 ml fat was taken and washed with PBS for 3 times to remove visible red blood cells. Then 0.075% type I collagenase of the same volume was added for 30–45 min digestion at 37 °C at 150 r/min, and DMEM/F12 medium containing 10%FBS was added to terminate digestion. After centrifugation, the top oil and intermediate clarifying solution are removed, and then the red blood cells are lysed with red blood cell lysate, followed by centrifugation to obtain a precipitate. The precipitate was resuspended in complete medium and filtered by 70 um cell sieve. After that, the resuspended solution was transferred to the culture dish for primary culture. ADSCs have the ability to differentiate into other mesoderm cells such as cardiomyocytes, endothelial cells, adipocytes, osteoblasts, chondrocytes, neuro-like cells
Fig. 3
Fig. 3
The three isolation techniques used in isolation of exosomes from serum-free conditioned media. (1) TEI the method where the serum-free conditioned media was taken and mixed with the reagent in 2:1 ratio, vortexed properly and incubated overnight at 4 °C. The exosomes were pelleted down at 10000 g for 60 min at 4 °C and were resuspended in 100 μl of 1 × PBS for further studies. (2) PROSPR is a technique that the conditioned media was mixed with ice-cold acetone in a ratio of 1:4 and vorutexed, then centrifuged at 3000 g for 2 min. The supernatant was collected and concentrated in a vacuum concentrator in vacuum-alcohol mode. The concentrated crystals were resuspended in 100 μl 1 × PBS. (3) The supernatant collected from this stage was centrifuged at 100000 g twice for 70 min each time to separate exosomes from the precipitation in the final step. The first hypervelocity rotation was to remove larger vesicles. The supernatant was discarded, and the precipitate was washed with 1× PBS in the second rotation. The resuspension of the precipitation is the same as before
Fig. 4
Fig. 4
The effect of ADSCs on the biological characteristics of fibroblasts and myofibroblasts during the process from wound to scar. The process of ADSCs in preventing scar formation is complex and has different roles in the wound stage and scar formation stage. In the wound stage, ADSCs and ADSCs-Exos increased the migration, proliferation, Col-I, Col-III, CD34, elastin, MMP3, decorin, keratinocyte of fibroblasts. In the scar stage, ADSCs and ADSC-Exos decreased the migration, proliferation, Col-I, Col-III, β-SMA, P-P38 protein, TIMP, differentiate of fibroblasts. However, they reduced α-SMA and TGF-β1 and inhibited the transformation of fibroblasts into myofibroblasts in both the wound and scar stage. “↑” and “↓” represent increase and decrease, respectively
Fig. 5
Fig. 5
The mechanism of effect of ADSCs and ADSC-Exos on the biological characteristics of fibroblasts and myofibroblasts. Four main mechanisms are summarized: (1) ADSCs and ADSC-Exos can inhibit the inflammatory response of macrophages and T cells, thereby attenuating the release of inflammatory factors, which in turn attenuates the response of fibroblasts and myofibroblasts to inflammation. (2) miRNA secreted by ADSCs and miRNA containde by ADSC-Exos can enter fibroblasts and myofibroblasts, then directly participate in the transcription and translation of genes. (3) ADSCs secrete various cytokines, which are involved in the regulation of fibroblasts and myofibroblasts through different signaling pathways. (4) ADSCs and ADSC-Exos promote angiogenesis, which enhance oxygen uptake by fibroblasts and myofibroblasts, then optimize the metabolism of fibroblasts and myofibroblasts. “­” and “+” stand for inhibition and promotion, respectively
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