The browning and mobilization of subcutaneous white adipose tissue supports efficient skin repair.

Adipocytes in dermis are considered to be important participants in skin repair and regeneration, but the role of subcutaneous white adipose tissue (sWAT) in skin repair is poorly understood. Here, we revealed the dynamic changes of sWAT during wound healing process. Lineage-tracing mouse studies revealed that sWAT would enter into the large wound bed and participate in the formation of granulation tissue. Moreover, sWAT undergoes beiging after skin injury. Inhibition of sWAT beiging by genetically silencing PRDM16, a key regulator to beiging, hindered wound healing process. The transcriptomics results suggested that beige adipocytes in sWAT abundantly express neuregulin 4 (NRG4), which regulated macrophage polarization and the function of myofibroblasts. In diabetic wounds, the beiging of sWAT was significantly suppressed. Thus, adipocytes from sWAT regulate multiple aspects of repair and may be therapeutic for inflammatory diseases and defective wound healing associated with aging and diabetes.

Brown adipose tissue transplantation improves skin fibrosis in localized scleroderma.

Adipose tissue transplantation shows great therapeutic potential in reversing localized scleroderma-associated skin fibrosis. Brown adipose tissue (BAT) can specifically secrete various cytokines against fibrosis, but its therapeutic potential in improving skin fibrosis has not yet been demonstrated. In this study, we have demonstrated the superior therapeutic efficacy of BAT transplantation for sclerotic skin by transplanting two distinct types of adipose tissue. In comparison to the white adipose tissue (WAT) group, mice treated with BAT transplantation exhibited a significant reduction in dermal thickness. BAT transplantation effectively reverses skin sclerosis through mechanisms involving inflammation reduction, promotion of angiogenesis, inhibition of myofibroblast accumulation, and collagen deposition. This therapeutic effect can be attributed to its unique paracrine effects. Furthermore, transcriptome sequencing (RNA-Seq) revealed upregulation of pathways associated with lipogenesis and fatty acid metabolism in BAT while downregulating pathways are related to transforming growth factor ß(TGF-ß), epithelial-mesenchymal transition (EMT), and inflammatory response. These findings suggest that BAT transplantation holds great promise as a novel approach for localized scleroderma treatment.

Physical Expansion Preconditioning Promotes Host-derived Adipocyte Dedifferentiation and Migration into Fat Grafts in A Murine Model.

BACKGROUND: The unstable recipient conditions after fat grafting remains an obstacle for tissue volumization. The interaction between fat grafts and recipient sites is not fully understood. We hypothesize that recipient-derived adipocytes undergo dedifferentiation and migrate into fat grafts in tissue regeneration. METHODS: To observe the participation from recipient fat pad, we established a recipient adipocyte-tracing model where 0.2 ml inguinal fat from ten 8-week-old C57BL/6 mice was grafted to ten tamoxifen-treated AdipoqCre;mT/mG mice. Next, to evaluate the impact of physical force on recipient fat and fat graft, murine internal expansion model was established by implanting a 1 ml internal expander upon the inguinal fat pad of the lineage tracing mice that received fat graft from C57BL/6 mice. Transplanted adipose tissue was collected and analyzed by immunostaining of GFP, tdTomato, perilipin, CD31. RESULTS: In the observing model, immunostaining revealed that both GFP+ and tdTomato+ cells from recipient fat pad presented in fat grafts. Among the GFP+ cells, most of them were perilipin+ adipocytes and other perilipin- cells co-expressed OCT4, indicating dedifferentiated adipocytes. In the internal expansion model, internal expansion increased GFP+ cells in fat graft. Both OCT4+/GFP+ (0.23 ± 0.01 vs. 0.12 ± 0.04) and perilipin+/GFP+ (0.17 ± 0.02 vs. 0.06 ± 0.01) cells were increased in the expanded group, compared with control. CONCLUSIONS: Host-derived adipocytes participate in fat graft regeneration through migration and dedifferentiation, which could be enhanced by internal expansion to increase fat graft retention rate. Further study using larger animal model is needed, since this is a murine study.

Dedifferentiated fat cells: current applications and future directions in regenerative medicine.

Stem cell therapy is the most promising treatment option for regenerative medicine. Therapeutic effect of different stem cells has been verified in various disease model. Dedifferentiated fat (DFAT) cells, derived from mature adipocytes, are induced pluripotent stem cells. Compared with ASCs and other stem cells, the DFAT cells have unique advantageous characteristics in their abundant sources, high homogeneity, easily harvest and low immunogenicity. The DFAT cells have shown great potential in tissue engineering and regenerative medicine for the treatment of clinical problems such as cardiac and kidney diseases, autoimmune disease, soft and hard tissue defect. In this review, we summarize the current understanding of DFAT cell properties and focus on the relevant practical applications of DFAT cells in cell therapy in recent years.

Internal Expansion Preconditioning of Recipient Site Increases Fat Graft Retention by Enriching Stem Cell Pool and Inducing Browning in Rats.

BACKGROUND: Fat grafting has an unsatisfactory retention rate for breast reconstruction due to poor recipient conditions. The contribution of the recipient site to fat grafts is unknown. In this study, we hypothesize that tissue expansion could improve fat graft retention by preconditioning the recipient fat fad. METHODS: Over-expansion was achieved using 10 ml cylindrical soft-tissue expanders implanted beneath the left inguinal fat flaps of 16 Sprague-Dawley rats (weighing 250-300 g), whose contralateral parts were implanted with a silicone sheet as control. After 7-days expansion, the implants were removed and both inguinal fat flaps received 1 ml of fat grafts from 8 donor rats. Fluorescent dye-labeled mesenchymal stromal cells (MSCs) were injected into rats and tracked in vivo by fluorescence imaging. Transplanted adipose tissue was harvested at 4 and 10 weeks (n = 8 per time point). RESULTS: After 7-days expansion, OCT4+ (p = 0.0002) and Ki67+ (p = 0.0004) positive area were increased with up-regulated expression of CXCL12 in recipient adipose flaps. An increasing number of DiI-positive MSCs were observed in the expanded fat pad. At 10 weeks after fat grafting, retention rate, measured using the Archimedes principle, was much higher in the expanded group than that in the non-expanded group (0.3019 ± 0.0680 vs. 0.1066 ± 0.0402, p = 0.0005). Histologic and transcriptional analyses revealed that angiogenesis was enhanced, and macrophage infiltration was decreased in the expanded group. CONCLUSIONS: Internal expansion preconditioning increased circulating stem cells into recipient fat pad and contributed to improved fat graft retention.

Corrigendum: Spontaneous browning of white adipose tissue improves angiogenesis and reduces macrophage infiltration after fat grafting in mice.

[This corrects the article DOI: 10.3389/fcell.2022.845158.].

The therapeutic effect of adipose-derived stem cells on soft tissue injury after radiotherapy and their value for breast reconstruction.

BACKGROUND: Postmastectomy radiotherapy is considered to be a necessary treatment in the therapy of breast cancer, while it will cause soft tissue damage and complications, which are closely related to the success rate and effectiveness of breast reconstruction. After radiotherapy, cutaneous tissue becomes thin and brittle, and its compliance decreases. Component fat grafting and adipose-derived stem cell therapy are considered to have great potential in treating radiation damage and improving skin compliance after radiotherapy. MAIN BODY: In this paper, the basic types and pathological mechanisms of skin and soft tissue damage to breast skin caused by radiation therapy are described. The 2015-2021 studies related to stem cell therapy in PubMed were also reviewed. Studies suggest that adipose-derived stem cells exert their biological effects mainly through cargoes carried in extracellular vesicles and soluble secreted factors. Compared to traditional fat graft breast reconstruction, ADSC therapy amplifies the effects of stem cells in it. In order to obtain a more purposeful therapeutic effect, proper stem cell pretreatment may achieve more ideal and safe results. CONCLUSION: Recent research works about ADSCs and other MSCs mainly focus on curative effects in the acute phase of radiation injury, and there is little research about treatment of chronic phase complications. The efficacy of stem cell therapy on alleviating skin fibrosis and its underlying mechanism require further research.

Ceiling culture of human mature white adipocytes with a browning agent: A novel approach to induce transdifferentiation into beige adipocytes.

Excess and dysfunctional adipose tissue plays an important role in metabolic diseases, including obesity, atherosclerosis and type 2 diabetes mellitus. In mammals, adipose tissue is categorized into two types: white and brown. Adult brown tissue is mainly composed of beige adipocytes, which dispose of stored energy as heat and have become increasingly popular as a therapeutic target for obesity. However, there is still a paucity of cell models that allow transdifferentiation of mature white adipocytes into beige adipocytes, as seen in vivo. Here, we describe a novel, ceiling culture-based model of human mature white adipocytes, which transdifferentiate into beige adipocytes under the mechanical force and hypoxia of ceiling culture. We also show that the use of rosiglitazone and rapamycin can modulate transdifferentiation, up and down regulating expression of beige adipocyte-specific genes, respectively. Rosiglitazone additionally facilitated the upregulation of fatty acid lipolysis and oxidation genes. Finally, these beige adipocytes derived from dedifferentiated adipocytes exhibited a progenitor-specific phenotype, with higher expression of mature adipocyte-specific genes than adipocyte-derived stem cells. Overall, we report a novel approach to conveniently cultivate beige adipocytes from white adipocytes in vitro, suitable for mechanistic studies of adipose biology and development of cell and drug therapies in the future.

Corrigendum: Spontaneous browning of white adipose tissue improves angiogenesis and reduces macrophage infiltration after fat grafting in mice.

[This corrects the article DOI: 10.3389/fcell.2022.845158.].

Spontaneous Browning of White Adipose Tissue Improves Angiogenesis and Reduces Macrophage Infiltration After Fat Grafting in Mice.

Background: Fat grafting is a frequently used technique; however, its survival/ regeneration mechanism is not fully understood. The browning of white adipocytes, a process initiated in response to external stimuli, is the conversion of white to beige adipocytes. The physiologic significance of the browning of adipocytes following transplantation is unclear. Methods: C57BL/6 mice received 150 mg grafts of inguinal adipose tissue, and then the transplanted fat was harvested and analyzed at different time points to assess the browning process. To verify the role of browning of adipocytes in fat grafting, the recipient mice were allocated to three groups, which were administered CL316243 or SR59230A to stimulate or suppress browning, respectively, or a control group after transplantation. Results: Browning of the grafts was present in the center of each as early as 7 days post-transplantation. The number of beige cells peaked at day 14 and then decreased gradually until they were almost absent at day 90. The activation of browning resulted in superior angiogenesis, higher expression of the pro-angiogenic molecules vascular endothelial growth factor A (VEGF-A) and fibroblast growth factor 21 (FGF21), fewer macrophages, and ultimately better graft survival (Upregulation, 59.17% ± 6.64% vs. Control, 40.33% ± 4.03%, *p < 0.05), whereas the inhibition of browning led to poor angiogenesis, lower expression of VEGF-A, increased inflammatory macrophages, and poor transplant retention at week 10 (Downregulation, 20.67% ± 3.69% vs. Control, 40.33% ± 4.03%, *p < 0.05). Conclusion: The browning of WAT following transplantation improves the survival of fat grafts by the promotion of angiogenesis and reducing macrophage.