Paracrine effects of stem cells in wound healing and cancer progression

Dittmer, Jürgen; Leyh, Benjamin

doi:10.3892/ijo.2014.2385

Cited by 71 publications

(47 citation statements)

References 120 publications

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“…In the case of wound healing, uMSCs attenuate tissue damage, inhibit fibrotic remodeling and apoptosis, promote angiogenesis, stimulate endogenous stem cell recruitment and proliferation, and reduce immune responses. However, the prevalent hypothesis has shown that, when used in cell-based therapy, uMSCs mainly provide benefits for wound healing via paracrine mechanisms [18,32]. Despite the early accumulation of systemically administered uMSCs at the site of injury, few uMSCs become permanently engrafted within the tissue.…”

Section: Discussionmentioning

confidence: 99%

Umbilical Cord-Derived Mesenchymal Stem Cell-Derived Exosomal MicroRNAs Suppress Myofibroblast Differentiation by Inhibiting the Transforming Growth Factor-β/SMAD2 Pathway During Wound Healing

Fang

Zhang

et al. 2016

Stem Cells Translational Medicine

452

331

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Excessive scar formation caused by myofibroblast aggregations is of great clinical importance during skin wound healing. Studies have shown that mesenchymal stem cells (MSCs) can promote skin regeneration, but whether MSCs contribute to scar formation remains undefined. We found that umbilical cord-derived MSCs (uMSCs) reduced scar formation and myofibroblast accumulation in a skin-defect mouse model. We found that these functions were mainly dependent on uMSC-derived exosomes (uMSC-Exos) and especially exosomal microRNAs. Through high-throughput RNA sequencing and functional analysis, we demonstrated that a group of uMSC-Exos enriched in specific microRNAs (miR-21, -23a, -125b, and -145) played key roles in suppressing myofibroblast formation by inhibiting the transforming growth factor-b2/SMAD2 pathway. Finally, using the strategy we established to block miRNAs inside the exosomes, we showed that these specific exosomal miRNAs were essential for the myofibroblast-suppressing and anti-scarring functions of uMSCs both in vitro and in vivo. Our study revealed a novel role of exosomal miRNAs in uMSC-mediated therapy, suggesting that the clinical application of uMSC-derived exosomes might represent a strategy to prevent scar formation during wound healing. STEM CELLS TRANSLATIONAL MEDICINE 2016;5:1425-1439 SIGNIFICANCEExosomes have been identified as a new type of major paracrine factor released by umbilical cordderived mesenchymal stem cells (uMSCs). They have been reported to be an important mediator of cell-to-cell communication. However, it is still unclear precisely which molecule or group of molecules carried within MSC-derived exosomes can mediate myofibroblast functions, especially in the process of wound repair. The present study explored the functional roles of uMSC-exosomal microRNAs in the process of myofibroblast formation, which can cause excessive scarring. This is an unreported function of uMSC exosomes. Also, for the first time, the uMSC-exosomal microRNAs were examined by high-throughput sequencing, with a group of specific microRNAs (miR-21, miR-23a, miR-125b, and miR-145) found to play key roles in suppressing myofibroblast formation by inhibiting excess a-smooth muscle actin and collagen deposition associated with activity of the transforming growth factor-b/SMAD2 signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Umbilical Cord-Derived Mesenchymal Stem Cell-Derived Exosomal MicroRNAs Suppress Myofibroblast Differentiation by Inhibiting the Transforming Growth Factor-β/SMAD2 Pathway During Wound Healing

Fang

Zhang

et al. 2016

Stem Cells Translational Medicine

452

331

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“…Hence, MVs may provide a novel means for the development of prospective strategies of cell-free regenerative therapies ultimately aiming to tackle otherwise intractable pathologies, improve age-related health span and mitigate the effects of degenerative diseases by tissue regeneration [36]. …”

Section: Mode Of Actionmentioning

confidence: 99%

Microvesicles as Vehicles for Tissue Regeneration: Changing of the Guards

et al. 2016

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Purpose of ReviewMicrovesicles (MVs) have been recognised as mediators of stem cell function, enabling and guiding their regenerative effects.Recent FindingsMVs constitute one unique size class of extracellular vesicles (EVs) directly shed from the cell plasma membrane. They facilitate cell-to-cell communication via intercellular transfer of proteins, mRNA and microRNA (miRNA). MVs derived from stem cells, or stem cell regulatory cell types, have proven roles in tissue regeneration and repair processes. Their role in the maintenance of healthy tissue function throughout the life course and thus in age related health span remains to be elucidated.SummaryUnderstanding the biogenesis and mechanisms of action of MVs may enable the development of cell-free therapeutics capable of assisting in tissue maintenance and repair for a variety of age-related degenerative diseases. This review critically evaluates recent work published in this area and highlights important new findings demonstrating the use of MVs in tissue regeneration.

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“…The use of epithelial cells in tissue restoration and wound healing has attracted considerable interest. As such, the number of studies that seek to employ epithelial cells with high therapeutic potential to create novel therapies that can target and ultimately restore tissue integrity has been increasing (2)(3)(4). Chronic cutaneous wounds are one of the most unfavorable pathophysiological processes in dermatologic surgery; however, they may be treated using cell-based therapy development (5).…”

Section: Introductionmentioning

confidence: 99%

Hair follicle units promote re-epithelialization in chronic cutaneous wounds: A clinical case series study

Liu

Zhao

2015

Experimental and Therapeutic Medicine

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Abstract. Chronic cutaneous wounds are one of the most unfavorable pathophysiological processes in routine practice. However, developments in hair follicle unit therapy may aid the treatment of these wounds. The aim of the present study was to investigate the function of hair follicle units in chronic cutaneous wound re-epithelialization and to develop an effective protocol for wound treatment. A total of 14 patients, of which nine were male and five were female, with a mean age of 60.71 years (range, 19-76 years) and a mean wound area of 74.14 cm 2 , were treated in the study. The hair follicle units were dissected from a scalp graft and transplanted into the chronic cutaneous wound bed, after which clinical evaluation was performed. Images of the recipient site were captured at 0, 1, 2, 3, 4, 5, 8 and 14 weeks following transplantation. In addition, histological examinations were conducted postoperatively at week 16. Total wound re-epithelialization was observed in all the patients. Histological analysis revealed that the epidermis and papillary dermis were present in the wound area. Adnexal structures and the reticular dermis were also observed. Therefore, the present study demonstrated the ability of hair follicle units to promote chronic cutaneous wound healing.

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Paracrine effects of stem cells in wound healing and cancer progression

Cited by 71 publications

References 120 publications

Umbilical Cord-Derived Mesenchymal Stem Cell-Derived Exosomal MicroRNAs Suppress Myofibroblast Differentiation by Inhibiting the Transforming Growth Factor-β/SMAD2 Pathway During Wound Healing

Umbilical Cord-Derived Mesenchymal Stem Cell-Derived Exosomal MicroRNAs Suppress Myofibroblast Differentiation by Inhibiting the Transforming Growth Factor-β/SMAD2 Pathway During Wound Healing

Microvesicles as Vehicles for Tissue Regeneration: Changing of the Guards

Hair follicle units promote re-epithelialization in chronic cutaneous wounds: A clinical case series study

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