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Abstract Background Mesenchymal stem cells (MSCs) can improve cutaneous wound healing via the secretion of growth factors. However, the therapeutic efficacy of MSCs varies depending upon their source. Induced pluripotent stem cells are emerging as a promising source of MSCs with the potential to overcome several limitations of adult MSCs. This study compared the effectiveness of conditioned medium of MSCs derived from induced pluripotent stem cells (iMSC-CdM) with that derived from umbilical cord MSCs (uMSC-CdM) in a mouse cutaneous wound healing model. We also investigated the mechanisms of protection. Methods The iMSC-CdM or uMSC-CdM were topically applied to mice cutaneous wound model. The recovery rate, scar formation, inflammation and angiogenesis were measured. We compared angiogenesis cytokine expression between iMSC-CdM and uMSC-CdM and their protective effects on human umbilical vein endothelial cells (HUVECs) under H2O2-induced injury. The effects of iMSC-CdM on energy metabolism, mitochondria fragmentation and apoptosis were measured. Results Topical application of iMSC-CdM was superior to the uMSC-CdM in accelerating wound closure and enhancing angiogenesis. Expression levels of angiogenetic cytokines were higher in iMSC-CdM than they were in uMSC-CdM. The iMSC-CdM protected HUVECs from H2O2 induced injury more effectively than uMSC-CdM did. Administration of iMSC-CdM stimulated HUVEC proliferation, tube formation and energy metabolism via the ERK pathway. Mechanistically, iMSC-CdM inhibited H2O2-induced mitochondrial fragmentation and apoptosis of HUVECs. Conclusion Collectively, these findings indicate that iMSC-CdM is more effective than uMSC-CdM in treating cutaneous wounds, and in this way, iMSC-CdM may serve as a more constant and sustainable source for cell-free therapeutic approach. Graphical abstract

Background: Mesenchymal stem cells (MSCs) can improve cutaneous wound healing via the secretion of growth factors. However, the therapeutic efficacy of MSCs varies depending upon their source. Induced pluripotent stem cells are emerging as a promising source of MSCs with the potential to overcome several limitations of adult MSCs. This study compared the effectiveness of conditioned medium of MSCs derived from induced pluripotent stem cells (iMSC-CdM) with that derived from umbilical cord MSCs (uMSC-CdM) in a mouse cutaneous wound healing model. We also investigated the mechanisms of protection. Methods: The iMSC-CdM or uMSC-CdM were topically applied to mice cutaneous wound model. The recovery rate, scar formation, inflammation and angiogenesis were measured. We compared angiogenesis cytokine expression between iMSC-CdM and uMSC-CdM and their protective effects on human umbilical vein endothelial cells (HUVECs) under H2O2-induced injury. The effects of iMSC-CdM on energy metabolism, mitochondria fragmentation and apoptosis were measured. Results: Topical application of iMSC-CdM was superior to the uMSC-CdM in accelerating wound closure and enhancing angiogenesis. Expression levels of angiogenetic cytokines were higher in iMSC-CdM than they were in uMSC-CdM. The iMSC-CdM protected HUVECs from H2O2 induced injury more effectively than uMSC-CdM did. Administration of iMSC-CdM stimulated HUVEC proliferation, tube formation and energy metabolism via the ERK pathway. Mechanistically, iMSC-CdM inhibited H2O2-induced mitochondrial fragmentation and apoptosis of HUVECs. Conclusion: Collectively, these findings indicate that iMSC-CdM is more effective than uMSC-CdM in treating cutaneous wounds, and in this way, iMSC-CdM may serve as a more constant and sustainable source for cell-free therapeutic approach. [ABSTRACT FROM AUTHOR]

Abstract Background It has been demonstrated previously that induced pluripotent stem cell (iPSC)-derived mesenchymal stem cells (MSCs) have immunosuppressive effects on activated T cells. However, the effects of iPSC-MSCs on quiescent T cells are still unknown. The aim of this study was to identify the immunomodulatory role of iPSC-MSCs on resting peripheral blood mononuclear cells (PBMCs) from allergic rhinitis (AR) patients. Methods PBMCs were cocultured with iPSC-MSCs without any stimulation, following which lymphocyte proliferation, activation of T cells, TH1/TH2 and regulatory T (Treg) cell differentiation, and Treg cell function were analyzed. The roles of soluble factors and cell–cell contact were examined to investigate the mechanisms involved. Results iPSC-MSCs promoted the proliferation of resting lymphocytes, activated CD4+ and CD8+ T cells, and upregulated and activated Treg cells without any additional stimulation. In addition, iPSC-MSCs balanced biased TH1/TH2 cytokine levels. Cell–cell contact was confirmed to be a possible mechanism involved. NF-κB was identified to play an important role in the immunomodulatory effects of iPSC-MSCs on quiescent T cells. Conclusions iPSC-MSCs activate quiescent T cells and elevate regulatory T-cell response in AR patients, suggesting different immunomodulatory functions of iPSC-MSCs according to the phases of diseases. Therefore, iPSC-MSCs are a potential therapeutic candidate for treating allergic airway inflammation.

Hypoxia is a serious stress state. The nervous system is less tolerant to hypoxia, and cell death due to hypoxia is irreversible. With the incidence of cardiovascular disease gradually increasing, the sudden cardiac death rate is additionally increasing. Although cardiopulmonary resuscitation (CPR) is an important development, recovery is frequently poor. In a successful recovery population, ~40% of the population was in a vegetative state or subsequently succumbed to their condition, and ~20% had brain damage. Therefore, the recovery of the brain is of particular importance in CPR. Immune disorders are one of the major mechanisms of cerebral resuscitation following CPR. Studies have demonstrated that induced pluripotent stem cell‑derived mesenchymal stem cells (IPSC‑MSCs) have a strong immune regulatory effect during tissue repair and anti‑inflammatory effects. IPSC‑MSCs may inhibit the inflammatory response by means of the inflammatory reaction network to improve brain function following CPR, although the cellular and molecular mechanisms remain unclear. Macrophages are a bridge between innate immune and specific immune responses in the body; therefore, it was hypothesized that macrophages may be the important effector cell of the role of IPSC‑MSCs in improving brain function following recovery of spontaneous respiration and circulation subsequent to cardiopulmonary resuscitation. In the present study, IPSC‑MSCs were applied to the oxygen and glucose deprivation (OGD) model. It was observed that intervention with IPSC‑MSCs was able to alter the polarization direction of macrophages. The difference in the proportions of M1 and M2 macrophages was statistically significant at 6, 12, 24 and 48 h (P=0.037, P<0.05) in the OGD + IPSC‑MSCs group (M1, 33.48±5.6%; M2, 50.84±6.9%) and in the OGD group (M1, 83.55±7.3%; M2, 11.41±3.2%), and over time this trend was more obvious. The polarization direction of macrophages is associated with the neurogenic locus notch homolog protein 1 (Notch‑1) signaling pathway. In conclusion, it was observed that IPSC‑MSCs may be associated with altered macrophage polarization, which may be accomplished by inhibiting the Notch‑1 signaling pathway. [ABSTRACT FROM AUTHOR]

Osteoporosis is a disease characterized by the degeneration of bone structure and decreased bone mass. Induced pluripotent stem cell-derived mesenchymal stem cells (iPSC-MSCs) have multiple advantages that make them ideal seed cells for bone regeneration, including high-level proliferation, multi-differentiation potential and favorable immune compatibility. Distal-less homeobox (DLX)3, an important member of the DLX family, serves a crucial role in osteogenic differentiation and bone formation. The present study aimed to evaluate the effects of DLX3 on the proliferation and osteogenic differentiation of human iPSC-MSCs. iPSC-MSCs were induced from iPSCs, and identified via flow cytometry. Alkaline phosphatase (ALP), Von Kossa, Oil Red O and Alcian blue staining methods were used to evaluate the osteogenic, adipogenic and chondrogenic differentiation of iPSC-MSCs. DLX3 overexpression plasmids were constructed and transfected into iPSC-MSCs to generate iPSC-MSC-DLX3. iPSC-MSC-GFP was used as the control. Reverse transcription-quantitative PCR (RT-qPCR) and western blotting were performed to measure the expression of DLX3 2 days after transfection. Subsequently, cell proliferation was assessed using a Cell Counting Kit-8 assay on days 1, 3, 5 and 7. RT-qPCR and western blotting were used to analyze osteogenic-related gene and protein expression levels on day 7. ALP activity and mineralized nodules were assessed via ALP staining on day 14. Statistical analysis was performed using an unpaired Student's t-test. Flow cytometry results demonstrated that iPSC-MSCs were positive for CD73, CD90 and CD105, but negative for CD34 and CD45. iPSC-MSC-DLX3 had significantly lower proliferation compared with iPSC-MSC-GFP on days 5 and 7 (P<0.05). mRNA expression levels of osteogenic markers, such as ALP, osteopenia (OPN), osteocalcin (OCN) and Collagen Type I (COL-1), were significantly increased in iPSC-MSC-DLX3 compared with iPSC-MSC-GFP on day 7 (P<0.05). Similarly, the protein expression levels of ALP, OCN, OPN and COL-1 were significantly increased in iPSC-MSC-DLX3 compared with iPSC-MSC-GFP on day 7 (P<0.05). The number of mineralized nodules in iPSC-MSC-DLX3 was increased compared with that in iPSC-MSC-GFP on day 14 (P<0.05). Thus, the present study demonstrated that DLX3 serves a negative role in proliferation, but a positive role in the osteogenic differentiation of iPSC-MSCs. This may provide novel insight for treating osteoporosis. [ABSTRACT FROM AUTHOR]