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1.
Stem Cells Dev ; 33(11-12): 262-275, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38717965

RESUMO

Type 2 diabetes mellitus (T2DM) is associated with endothelial dysfunction, which results in delayed wound healing. Mesenchymal stem cells (MSCs) play a vital role in supporting endothelial cells (ECs) and promoting wound healing by paracrine effects through their secretome-containing extracellular vesicles. We previously reported the impaired wound healing ability of adipose tissue-derived MSC from T2DM donors; however, whether extracellular vesicles isolated from T2DM adipose tissue-derived MSCs (dEVs) exhibit altered functions in comparison to those derived from healthy donors (nEVs) is still unclear. In this study, we found that nEVs induced EC survival and angiogenesis, whereas dEVs lost these abilities. In addition, under high glucose conditions, nEV protected ECs from endothelial-mesenchymal transition (EndMT), whereas dEV significantly induced EndMT by activating the transforming growth factor-ß/Smad3 signaling pathway, which impaired the tube formation and in vivo wound healing abilities of ECs. Interestingly, the treatment of dEV-internalized ECs with nEVs rescued the induced EndMT effects. Of note, the internalization of nEV into T2DM adipose tissue-derived MSC resulted in the production of an altered n-dEV, which inhibited EndMT and supported the survival of T2DM db/db mice from severe wounds. Taken together, our findings suggest the role of dEV in endothelial dysfunction and delayed wound healing in T2DM by the promotion of EndMT. Moreover, nEV treatment can be considered a promising candidate for cell-free therapy to protect ECs in T2DM.


Assuntos
Diabetes Mellitus Tipo 2 , Células Endoteliais , Vesículas Extracelulares , Glucose , Células-Tronco Mesenquimais , Transdução de Sinais , Proteína Smad3 , Fator de Crescimento Transformador beta , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/citologia , Vesículas Extracelulares/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Humanos , Fator de Crescimento Transformador beta/metabolismo , Proteína Smad3/metabolismo , Glucose/metabolismo , Glucose/farmacologia , Animais , Camundongos , Células Endoteliais/metabolismo , Masculino , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Transição Epitelial-Mesenquimal , Cicatrização , Feminino , Células Cultivadas , Células Endoteliais da Veia Umbilical Humana/metabolismo , Transição Endotélio-Mesênquima
2.
Stem Cells Dev ; 32(19-20): 592-605, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37392019

RESUMO

Glucocorticoids are common anti-inflammatory factors; however, they have been reported to have side effects that delay the wound healing process. In a previous study, we found that mesenchymal stem cells isolated from the adipose tissue of patients with long-term glucocorticoid treatment (sAT-MSC) showed impaired wound healing ability due to the downregulation of SDF-1. In this study, we aimed to clarify the mechanisms by which SDF-1 is regulated in sAT-MSC by focusing on the roles of hypoxia-inducible factors (HIFs). Our data suggested that sAT-MSC showed impairment of HIF-1α and the upregulation of HIF-2α. Notably, HIF-2α impairment resulted in the compensatory overexpression of HIF-1α and its target gene SDF-1, which improved the wound healing ability of sAT-MSC. In addition, using knockdown/knockout heterozygous HIF-2α kd/null mice (kd/null), the functions of HIF-2α in the ischemic wound healing process were clarified. With a 50% reduction in the expression of HIF-2α, kd/null mice showed significantly induced wound healing effects, which are involved in the promotion of the inflammatory phase. Specifically, kd/null mice showed the compensatory overexpression of HIF-1α, which upregulated the expression of SDF-1 and enhanced the recruitment of inflammatory cells, such as neutrophils. Our study highlighted the novel function of HIF-2α in the inflammation phase of the wound healing process through the HIF-1α/SDF-1 axis, suggesting that the physiological state of the impaired expression of HIF-2α is a new concept for wound therapy.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos , Células-Tronco Mesenquimais , Animais , Humanos , Camundongos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Células-Tronco Mesenquimais/metabolismo , Ativação Transcricional , Regulação para Cima , Cicatrização/genética
3.
Sci Rep ; 12(1): 13550, 2022 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-35941273

RESUMO

Triple negative breast cancer (TNBC) is associated with worse outcomes and results in high mortality; therefore, great efforts are required to find effective treatment. In the present study, we suggested a novel strategy to treat TNBC using mesenchymal stem cell (MSC)-derived extracellular vesicles (EV) to transform the behaviors and cellular communication of TNBC cells (BCC) with other non-cancer cells related to tumorigenesis and metastasis. Our data showed that, BCC after being internalized with EV derived from Wharton's Jelly MSC (WJ-EV) showed the impaired proliferation, stemness properties, tumorigenesis and metastasis under hypoxic conditions. Moreover, these inhibitory effects may be involved in the transfer of miRNA-125b from WJ-EV to BCC, which downregulated the expression of HIF1α and target genes related to proliferation, epithelial-mesenchymal transition, and angiogenesis. Of note, WJ-EV-internalized BCC (wBCC) showed transformed behaviors that attenuated the in vivo development and metastatic ability of TNBC, the angiogenic abilities of endothelial cells and endothelial progenitor cells and the generation of cancer-associated fibroblasts from MSC. Furthermore, wBCC generated a new EV with modified functions that contributed to the inhibitory effects on tumorigenesis and metastasis of TNBC. Taken together, our findings suggested that WJ-EV treatment is a promising therapy that results in the generation of wBCC to interrupt the cellular crosstalk in the tumor environment and inhibit the tumor progression in TNBC.


Assuntos
Vesículas Extracelulares , Células-Tronco Mesenquimais , MicroRNAs , Neoplasias de Mama Triplo Negativas , Geleia de Wharton , Carcinogênese/genética , Carcinogênese/metabolismo , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Células Endoteliais , Humanos , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/metabolismo , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/terapia , Geleia de Wharton/metabolismo
4.
Stem Cells Dev ; 31(21-22): 659-671, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35734905

RESUMO

Triple-negative breast cancer (TNBC) is a highly aggressive and invasive type of breast cancer. In addition, type 2 diabetes mellitus (T2DM) is recognized as a risk factor for cancer metastasis, which is associated with mortality in patients with breast cancer. Cancer-associated fibroblasts (CAFs) generated from adipose tissue-derived mesenchymal stem cells (AT-MSCs) play a vital role in the progression of TNBC. However, to date, whether T2DM affects the ability of AT-MSCs to differentiate into CAFs is still unclear. In this study, we found that in coculture with TNBC cells [breast cancer cells (BCCs)] under hypoxic conditions, AT-MSCs derived from T2DM donors (dAT-MSCs) were facilitated to differentiate into CAFs, which showed fibroblastic morphology and the induced expression of fibroblastic markers, such as fibroblast activation protein, fibroblast-specific protein, and vimentin. This was involved in the higher expression of transforming growth factor beta receptor 2 (TGFßR2) and the phosphorylation of Smad2/3. Furthermore, T2DM affected the fate and functions of CAFs derived from dAT-MSCs. While CAFs derived from AT-MSCs of healthy donors (AT-CAFs) exhibited the markers of inflammatory CAFs, those derived from dAT-MSCs (dAT-CAFs) showed the markers of myofibroblastic CAFs. Of note, in comparison with AT-CAFs, dAT-CAFs showed a higher ability to induce the proliferation and in vivo metastasis of BCCs, which was involved in the activation of the transforming growth factor beta (TGFß)-Smad2/3 signaling pathway. Collectively, our study suggests that T2DM contributes to metastasis of BCCs by inducing the myofibroblastic CAFs differentiation of dAT-MSCs. In addition, targeting the TGFß-Smad2/3 signaling pathway in dAT-MSCs may be useful in cancer therapy for TNBC patients with T2DM.


Assuntos
Neoplasias da Mama , Fibroblastos Associados a Câncer , Diabetes Mellitus Tipo 2 , Células-Tronco Mesenquimais , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias da Mama/patologia , Diabetes Mellitus Tipo 2/metabolismo , Linhagem Celular Tumoral , Fibroblastos , Fator de Crescimento Transformador beta/metabolismo
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