Background Tendon stem cells (TSCs) have been reported to hold promises for tendon repair and regeneration. However, less is known about the effects of exosomes derived from TSCs. Therefore, we aimed to clarify the healing effects of TSC-derived exosomes (TSC-Exos) on tendon injury. Methods The Achilles tendons of Sprague-Dawley male rats were used for primary culture of TSCs and tenocytes, and exosomes were isolated from TSCs. The proliferation of tenocytes induced by TSC-Exos was analyzed using an EdU assay; cell migration was measured by cell scratch and transwell assays. We used western blot to analyze the role of the PI3K/AKT and MAPK/ERK1/2 signaling pathways. In vivo, Achilles tendon injury models were created in Sprague-Dawley rats. Rats (n = 54) were then randomly assigned to three groups: the TSC-Exos group, the GelMA group, and the control group. We used immunofluorescence to detect changes in the expression of inflammatory and apoptotic markers at 1 week after surgery. Histology and changes in expression of extracellular matrix (ECM)-related indices were assessed by hematoxylin-eosin (H&E) staining and immunohistochemistry at 2 and 8 weeks. The collagen fiber diameter of the healing tendon was analyzed at 8 weeks by transmission electron microscopy (TEM). Results TSC-Exos were taken up by tenocytes, which promoted the proliferation and migration of cells in a dose-dependent manner; this process may depend on the activation of the PI3K/AKT and MAPK/ERK1/2 signaling pathways. At 1 week after surgery, we found that inflammation and apoptosis were significantly suppressed by TSC-Exos. At 2 and 8 weeks, tendons treated with TSC-Exos showed more continuous and regular arrangement in contrast to disorganized tendons in the GelMA and control groups, and TSC-Exos may help regulate ECM balance and inhibited scar formation. Further, at 8 weeks, the TSC-Exos group had a larger diameter of collagen compared to the control group. Conclusions Our data suggest that TSC-Exos could promote high-quality healing of injured tendon, which may be a promising therapeutic approach for tendon injury.

As a component of p53-dependent lncRNA (long non-coding RNA), PANDAR (the promoter of CDKN1A antisense DNA damage activated RNA) participates in the epigenetic regulation in human cancer. However, the involvement of PANDAR in cancer chemoresistance is unknown. In this study, we report that PANDAR serves as a negative regulator of cisplatin sensitivity in human ovarian cancer via PANDAR-SRFS2-p53 feedback regulation in nuclear. Our data showed that among the drugs commonly used in ovarian cancer therapy, cisplatin induces higher levels of PANDAR compared with doxorubicin and paclitaxel. We also proved that PANDAR exhibited higher expression in cisplatin-resistant ovarian cancer tissues and cells, compared with cisplatin-sensitive ones, and this expression pattern depends on wild-type p53 (wt-p53), not mutant-p53 (mt-p53). In vitro and in vivo, PANDAR overexpression improved cell survival rate and tumor growth in response to cisplatin, while depletion of PANDAR leads to a reduced tumor growth. Further investigation revealed that PANDAR-reduced cisplatin sensitivity was likely or partly due to the PANDAR-binding protein SFRS2 (arginine/serine-rich 2), a splicing factor with the ability to negative regulate p53 and its phosphorylation at Serine 15 (Ser15). This feedback regulation of PANDAR–SFRS2–p53 leads to a reduced transactivation of p53-related pro-apoptotic genes, such as PUMA (p53-upregulated modulator of apoptosis). In addition, in platinum-treated patients with relapsed ovarian cancer, resistant period was positively correlated with the expression of PANDAR and SFRS2, and inversely associated with expression of p53-Ser15 and PUMA in these clinical tissues. Last but not least, the role of PANDAR in chemoresistance was confirmed in patients with ovarian cancer. These findings reveal a novel regulatory maneuver of cancer cells in response to chemostress, and might shed light on overcoming cisplatin resistance in ovarian cancer.

Combining the use of TNF-α and TGF-β1 could improve the proliferation and differentiation of TDSC in vitro, and the expression of I-Smad is negatively correlated with TDSC proliferation and differentiation.

To study the effects of the donor age on the application potential of human urine-derived stem cells (hUSCs) in bone tissue engineering, by comparing proliferation, senescence and osteogenic differentiation of hUSCs originated from volunteers with different ages. The urine samples were collected from 19 healthy volunteers (6 cases from children group aged from 5 to 14, 5 cases from middle-aged group aged from 30 to 40, and 8 cases from the elder group aged from 65 to 75), and hUSCs were isolated and cultured. The cell morphology was observed by microscope and the cell surface markers were identified by flow cytometry. Their abilities to undergo osteogenic, adipogenic and chondrogenic differentiation were determined in vitro, and cell proliferation analyses were performed using Cell Counting Kit-8 (CCK8) Assay. The senescence of hUSCs among three groups was assessed by senescence-associated β galactosidase staining. After osteogenic differentiation, the alkaline phosphatase (ALP) activity of hUSCs was measured and expression of osteogenic-related runt-related transcription factor 2 (RUNX2) and osteocalcin (OCN) was determined by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. The hUSCs isolated from urine samples were adherent cells displayed "rice gain"-like and "spindle-shaped" morphology, expressing surface markers of mesenchymal stem cells (MSCs) (CD73, CD90, CD105) and the peripheral cell marker (CD146), but not hematopoietic stem cell markers (CD34, CD45) or the embryonic stem cell marker (OCT3/4). The obtained hUSCs could be induced into osteogenic, adipogenic or chondrogenic differentiation. The hUSCs from the children group showed higher proliferation and lower tendency to senescence than those from the middle-aged and elder groups. After osteogenic induction, the ALP activity and RUNX2 and OCN expression of hUSCs from the children group were higher than those from the elder group. While no significant differences were observed when comparing the middle-aged group with the children group or the elder group. Donor age could influence the potency of hUSCs on proliferation, senescence and capacity of osteogenic differentiation. hUSCs from children group have shown higher proliferation, lower tendency to senescence, and stronger osteogenic capacity, which means to be more suitable for basic research and have better clinical application. Furthermore, hUSCs from all groups suggest the application potential in bone tissue engineering as seed cells.

Heterotopic ossification is common in tendon healing after trauma, but the detailed mechanisms remain unknown. Tendon‐derived stem cells (TDSCs) are a type of progenitor cell found in the tendon niche, and their incorrect differentiation after trauma may lead to tendon calcification. The expression of hepatocyte growth factor (HGF) presents drastic fluctuations in serum/tissue after trauma and was found to activate quiescent stellate cells and contribute to wound healing; however, its potential role in TDSCs remains elusive. In this study, TDSCs isolated from rats were cultured in media containing HGF with or without a signaling inhibitor, and the proliferation, migration, and differentiation ability of TDSCs were measured to determine the role and mechanism of HGF in TDSCs. We showed that HGF promotes TDSC proliferation and migration but inhibits TDSC osteogenic differentiation ability. HGF activated‐HGF/c‐Met, mitogen‐activated protein kinase (MAPK)/extracellular signal‐regulated protein kinases 1 and 2 (ERK1/2), and phosphoinositide 3‐kinase (PI3K)/protein kinase B (AKT) signaling, which was positively correlated with TDSCs proliferation and migration but negatively related to TDSC osteogenic differentiation ability. The phosphorylation of Smad1/5/8 was also negatively related to HGF/c‐Met, MAPK/ERK1/2, and PI3K/AKT signaling, which demonstrated that the inhibition of osteogenic differentiation was dependent on BMP/Smad1/5/8 signaling. Overall, we showed that HGF could promote TDSCs proliferation and migration and inhibit osteogenic differentiation in vitro, suggesting a potential role for HGF as a cytokine treatment of tendon trauma.