Current Stem Cell Research & Therapy - Online First

Diabetic foot ulcer (DFU) is a severe complication of diabetes mellitus, affecting up to 15% of diabetic patients and leading to high rates of hospitalization, morbidity, and lower limb amputation.

This case study details the management of a 67-year-old diabetic male patient with a DFU complicated by osteomyelitis. The patient, with a long history of diabetes and multiple comorbidities, was treated with a comprehensive regimen that included antibiotics, debridement, and platelet-rich plasma (PRP) therapy. PRP was administered weekly for 15 weeks. Clinical, laboratory, and imaging data were employed for the evaluation of the disease improvement. As a result, a marked improvement in wound healing was observed, characterized by reduced wound size, accelerated closure of the wound, and enhanced tissue regeneration. However, the patient developed deep vein thrombosis, which was successfully managed with anticoagulants.

The study highlights PRP's potential in DFU treatment due to its regenerative properties despite the risk of adverse effects. The efficacy of PRP aligns with previous studies, showing improved healing rates and infection control. Future research should focus on large-scale trials to optimize PRP protocols and confirm the safety and efficacy of this therapeutic method in DFU.

Fetal Bovine Serum (FBS), the conventional supplement for Mesenchymal Stromal Cell (MSC) culture, presents ethical issues, batch variability, and risks of pathogen transmission. This study aimed to evaluate human-derived Umbilical Cord Serum (UCS) and Human Platelet Lysate (HPL) as xeno-free alternatives to FBS and to assess the synergistic effects of nano-curcumin and crocin as supplements to enhance the proliferation and survival of human umbilical cord-derived MSCs.

Human umbilical cord-derived MSCs were cultured in media supplemented with 10% FBS (control), UCS, or HPL. These groups were further treated with nano-curcumin (0.3 µM) or crocin (2.5 µM), either individually or in combination. Cell proliferation was measured using the MTT assay, apoptosis was assessed by Annexin V/PI flow cytometry, and pluripotency gene expression (Sox2, Nanog, Oct4) was analyzed by RT-qPCR.

UCS and HPL supplements significantly increased MSC proliferation compared to the FBS control (p < 0.001). Specifically, UCS reduced the population doubling time by approximately 50%. Supplementation with crocin reduced apoptosis by up to 30% (p = 0.04) and significantly enhanced the expression of the pluripotency genes Sox2 and Nanog, particularly in cultures supplemented with HPL. In contrast, nano-curcumin inhibited MSC proliferation and increased apoptosis across all tested conditions.

The results demonstrate that UCS and HPL are effective, viable alternatives to FBS, promoting superior MSC expansion. The anti-apoptotic and stemness-enhancing properties of crocin highlight its potential as a valuable additive for improving culture quality and cell survival. The cytotoxic effects observed with nano-curcumin underscore a critical need for dose-optimization studies. The primary limitation of this study is the use of fixed concentrations for the supplements, which warrants further investigation across a range of doses.

UCS and HPL are robust, ethically sound replacements for FBS in MSC biomanufacturing. Crocin can further enhance culture outcomes by improving cell survival and maintaining stemness. These findings support the development of optimized, xeno-free culture systems for scalable MSC production, which is crucial for advancing regenerative medicine therapies.

Exosomes produced by mesenchymal stem cells (MSCs) have lately garnered significant attention for their capacity to enhance wound healing. Recent studies have recognized exosomes as significant secretory products from several cell types, specifically MSCs, in regulating multiple biological processes, including wound healing. This work aims to investigate the impact of exosomes derived from the bone marrow mesenchymal stem cells (BMMSCs) of NMRI animals on keratinocyte function.

Exosomes were extracted from BMMSCs using a flushing technique and afterwards cultivated. Stem cells were detected via flow cytometry, while exosomes were isolated and purified through ultracentrifugation. The exosomes were analyzed using various techniques, including scanning electron microscopy (SEM), atomic force microscopy (AFM), transmission electron microscopy (TEM), and dynamic light scattering (DLS). The MTT assay and trypan blue staining were employed to assess the effect of exosomes on keratinocyte viability. A scratch assay was performed to evaluate cell migration after treatment with exosomes. Real-time PCR was employed to evaluate the expression of genes such as KGF, MMP3, VEGF, and TGF-β3.

Keratinocytes exposed to 10 µg/mL of exosomes exhibited markedly enhanced viability relative to the control group. The group treated with exosomes had more cell migration compared to the control group. The therapy group had elevated expression levels of the KGF, MMP3, VEGF, and TGF-β3 genes.

The experimental findings indicate that exosomes derived from BMMSCs enhance keratinocyte viability, proliferation, migration, and gene expression.

A comprehensive study of the factors affecting exosome generation, isolation, and mechanisms of action is crucial, as their potential use in wound healing facilitates the development of innovative and highly effective therapeutic strategies.

Stem cell therapies are advancing rapidly, requiring robust regulations to ensure safety and ethics. The UAE, with authorities like MOHAP, DOH, DHA, and DHCR, is actively involved in clinical research but faces regulatory inconsistencies across emirates. In contrast, the U.S. (FDA, NIH) and India (CDSCO, ICMR) have unified national frameworks with specific stem cell guidelines. This study compares the UAE’s system with those of the U.S. and India to identify strengths and gaps.

A comparative literature review was conducted using regulatory documents, clinical trial registries, peer-reviewed studies, and interviews. The focus was on analyzing the regulatory frameworks in the UAE, the U.S., and India, especially regarding stem cell clinical research.

The UAE has established ethical review boards and oversight mechanisms but lacks unified national guidelines and consistent application across emirates. In comparison, the U.S. and India have more cohesive, transparent, and accessible regulatory systems for stem cell research.

The UAE’s efforts in promoting stem cell research are notable, but fragmentation among regulatory authorities hampers coordination. Adopting centralized policies, like in the U.S. and India, could improve efficiency, transparency, and compliance. A national registry and stem cell-specific guidelines are also needed.

The UAE has made commendable progress in regulating stem cell clinical research. However, the absence of unified national guidelines and inter-emirate coordination remains a challenge. Learning from the centralized frameworks of the U.S. and India can help bridge these gaps. Strengthening oversight will enhance patient safety, ethical compliance, and global collaboration.

Cell therapy is regarded as a significant and therapeutic strategy for treating spinal cord injury (SCI). This systematic review was conducted to assess Schwann cell (SC) therapy and its effect on functional recovery, axonal regeneration, and remyelination.

By a systematic review study, all associated articles that investigated the effect of Schwann cell therapy on functional recovery, axonal regeneration and remyelination and were published between 1995 and 2024 were evaluated through searching in PubMed, Google Scholar, Scopus and Web of Science. The following keywords were searched: spinal cord injury, Schwann cell therapy, transplantation, functional recovery, axonal regeneration, and remyelination and Boolean operators were used to increase the search results: “(Remyelination OR Regeneration OR Transplantation) AND (Spinal Cord Injury)”, “Spinal Cord Injury AND Schwann cell”, “Spinal Cord Injury AND Schwann cell AND transplantation” and the search was filtered for species, injury type, experimental study, interventional study, clinical trial study, systematic review and meta-analysis study and was limited to articles in English and Persian languages.

The results of studies on animal samples showed significant functional recovery of cases treated using SCs. However, the success of cell therapy in human experiments has not been established; moreover, researchers should consider other therapeutic approaches in addition to cell transplantation, especially combination therapy.

Studies have shown that Schwann cell transplantation into a contused spinal cord can result in axonal regeneration and functional recovery, similar to the repair models involving spinal cord transection. Therefore, an understanding of the results of Schwann cell therapy on functional recovery, axonal regeneration, and remyelination in spinal cord injury is necessary and helpful.

Schwann cell transplantation promotes functional recovery and axonal regeneration in SCI animal models, but human translation requires further investigation, highlighting the need for combinatorial therapies.

Fibroblast growth factor 2 (FGF2) plays a crucial role in regulating the osteogenic differentiation of progenitor cells. However, the process by which this occurs is not yet fully understood. In this study, we aimed to investigate whether FGF2 stimulates the osteogenesis of precursor cells through the yes-associated protein (YAP) and large tumor suppressor kinases 1/2 (LATS1/2).

Human bone marrow stromal cells (hBMSCs) were cultured in osteogenic medium supplemented with FGF2 at concentrations of 2 ng/mL, 10 ng/mL, and 50 ng/mL for 2, 7, or 21 days. Alizarin red staining was performed to identify mineralization after 21 days of culture. RT-qPCR was conducted to detect the mRNA expression of Yap, Lats1, Lats2, Runx2, Bglap, and β-Actin. Immunofluorescence staining was carried out to detect the protein expression of YAP and LATS1/2. Data was analyzed with a p-value set at 0.05.

Mineralization was most significant at 10 ng/ml of FGF2 for 7 days and increased with concentrations of FGF2 from 0 ng/ml to 10 ng/ml for 7 days (p < 0.05) but decreased at the high concentration of 50 ng/ml for 2 days (p < 0.05). mRNA expression of Yap, Runx2, and Bglap increased in concordance with the increasing mineralization levels, but Lats1/2 mRNA decreased. mRNA expression levels were dose-dependent when FGF2 was added for 7 days (p < 0.05) and time-dependent when FGF2 concentration was at 10 ng/ml (p < 0.05). At the protein level, YAP increased while LATS1/2 decreased, indicating that LATS1/2 decreased, and YAP increased at higher mineralization levels when hBMSCs were cultured with 10 ng/ml of FGF2 for 7 days.

Consistent with our results, prior research has also indicated that lower concentrations of FGF2 enhance cell proliferation, thereby increasing the cell population for later osteogenic differentiation. However, excessive expansion can negatively affect differentiation. The mechanism of FGF2 regulation in stem cell osteogenic differentiation needs more exploration.

Optimal concentrations and durations of FGF2 are critical for the osteogenic differentiation of hBMSCs. Moreover, it has been observed that mineralization correlates well with increasing YAP and decreasing LATS1/2 during osteogenic differentiation.

Rheumatoid arthritis (RA) is an inflammatory disease that causes significant disability and persistent inflammation. Currently, there are no appropriate treatments for RA other than systemic immunosuppressants, which have a variety of undesirable effects after long-term use. Thus, this study aims to determine the anti-arthritis effect of chrysin (5,7-dihydroxyflavone) and/or bone marrow-derived mesenchymal stem cells (BM-MSCs), separately and combined, on CFA (complete Freund’s adjuvant)-induced arthritis in rats as an animal model of RA.

Male Wistar rats were subcutaneously injected with 100 μL of CFA/rat/day in the paw of the right hind limb for two consecutive days to induce RA. Arthritic rats received chrysin in an oral dose of 100 mg/kg bw each day, BM-MSCs at 1 × 10⁶ cells/rat once per week in DMEM (Dulbecco’s modified Eagle’s medium) into the lateral tail vein, and a combination for 21 days.

The oral administration of chrysin and intravenous injection of BM-MSCs significantly reduced the increased anteroposterior thickness, volume, and circumference of the right hind paw, as well as serum levels of RF, IL-1β, TNF-α, and IL-17, as well as serum MDA level, besides augmenting serum levels of GPx, GST, GSH, and SOD. The arthritic rats treated with chrysin and/or BM-MSCs exhibited a significant improvement in the elevated expression levels of IκBα, NF-κB p50, and NF-κB p65 proteins in ankle joint articular tissue. Similarly, the histopathological score and histological sections provided additional evidence of the improvement in arthritic lesions.

The treatment with chrysin and BM-MSCs has potential anti-arthritic effects, which may be attributed to their abilities to suppress the inflammation and oxidative stress and enhance the antioxidant defense system. The combinatory effect of chrysin and BM-MSCs was found to be the most effective. However, further clinical studies are required to assess their safety and efficacy in patients with arthritis.

Due to their strong antioxidant and anti-inflammatory properties, the combined administration of chrysin and BM-MSCs was found to be more effective in treating arthritis than either treatment alone in Wistar rats.