Human Umbilical Mesenchymal Stem Cells Research Articles

HGF secreted by hUC-MSCs mitigates neuronal apoptosis to repair the injured spinal cord via phosphorylation of Akt/FoxO3a pathway

Spinal cord injury (SCI) can cause severe and permanent neurological damage, and neuronal apoptosis could inhibit functional recovery of damaged spinal cord greatly. Human umbilical cord mesenchymal stem cells (hUC-MSCs) have great potential to repair SCI because of a series of advantages, including inhibition of neuronal apoptosis and multiple differentiation. The former may play an important role. However, the detailed regulatory mechanism associated with the inhibition of neuronal apoptosis after hUC-MSCs administration has not been elucidated. In this study, proteomics analysis of precious human cerebrospinal fluid (CSF) samples collected from SCI subjects receiving hUC-MSCs delivery indicated that hepatocyte growth factor (HGF) is largely involved in SCI repair. Furthermore, overexpression of HGF derived from hUC-MSCs could decrease reactive oxygen species to prevent neuron apoptosis to the maximum, and thus lead to significant recovery of spinal cord dysfunction. Moreover, HGF could promote phosphorylation of Akt/FoxO3a pathway to decrease reactive oxygen species to reduce neuron apoptosis. For the first time, our research revealed that HGF secreted by hUC-MSCs inhibits neuron apoptosis by phosphorylation of Akt/FoxO3a to repair SCI. This study provides important clues associated with drug selection for the effective treatment of SCI in humans.

Human umbilical cord mesenchymal stem cell-derived exosomes provide neuroprotection in traumatic brain injury through the lncRNA TUBB6/Nrf2 pathway

Recently, human umbilical cord mesenchymal stem cell (HucMSC) is a new focus of research in neurological diseases, and the beneficial effect of HucMSC is mediated by paracrine factors which are transported by exosome. Our previous study has shown that HucMSC-derived exosome could provide neuroprotection after traumatic brain injury (TBI). However, the underlying mechanisms were not fully understood. In the present study, we found that administration of exosome suppressed TBI-induced inflammation and ferroptosis. In addition, exosome activated the long non-coding ribonucleic acid (lncRNA) TUBB6/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway after TBI. However, exosome partly failed to provide neuroprotection following TBI when TUBB6 was knockdown. Importantly, exosome treatment also decreased neuron cell death, suppressed inflammation, inhibited ferroptosis and activated the lncRNA TUBB6/Nrf2 pathway after TBI in vitro. Taken together, our results provided the first evidence that HucMSC-derived exosome played a key role in neuroprotection after TBI through the lncRNA TUBB6/Nrf2 pathway.

The Effect of Giving Human Umbilical Cord Mesenchymal Stem Cells (HUMSC) on the Expression of Collagen I in Menopause Model Mice

Background: Patients with pelvic floor dysfunction (PFD) who fail conservative treatment will undergo surgery. In recent years, various therapeutic approaches for PFD using stem cells have been investigated in vivo. One component of stem cells is the human umbilical cord mesenchymal stem cell (HUMSC). It is hoped that HUMSC can modify the collagen and elastin content in the extracellular matrix, leading to improvements in pelvic floor strength and PFD.
 Methods: This research is an experimental study with a randomized posttest-only controlled group design with the aim of determining the effect of giving HUMSC on the expression of Collagen I in a female mouse model of menopause. There are inclusion criteria, namely female Balb/c mice, healthy, never mated, aged 8 - 12 weeks, and body weight 18 - 22 grams. The research will be carried out with statistical analysis using SPSS; a p-value <0.05 is considered significant.
 Results: The results of the analysis of the distribution of sample means show that there are significant differences between the two groups. The treatment group had a higher mean expression of type I collagen compared to the control group. In addition, variation in the control group was lower compared with the treatment group, which could be interpreted as higher consistency in the response to HUMSC treatment.
 Conclusion: Human umbilical cord (HUMSC) has a positive impact on type I collagen expression in menopausal model mice.

Hypoxia and inflammatory factor preconditioning enhances the immunosuppressive properties of human umbilical cord mesenchymal stem cells.

Mesenchymal stem cells (MSCs) have great potential for the treatment of various immune diseases due to their unique immunomodulatory properties. However, MSCs exposed to the harsh inflammatory environment of damaged tissue after intravenous transplantation cannot exert their biological effects, and therefore, their therapeutic efficacy is reduced. In this challenging context, an in vitro preconditioning method is necessary for the development of MSC-based therapies with increased immunomodulatory capacity and transplantation efficacy. To determine whether hypoxia and inflammatory factor preconditioning increases the immunosuppressive properties of MSCs without affecting their biological characteristics. Umbilical cord MSCs (UC-MSCs) were pretreated with hypoxia (2% O2) exposure and inflammatory factors (interleukin-1β, tumor necrosis factor-α, interferon-γ) for 24 h. Flow cytometry, polymerase chain reaction, enzyme-linked immunosorbent assay and other experimental methods were used to evaluate the biological characteristics of pretreated UC-MSCs and to determine whether pretreatment affected the immunosuppressive ability of UC-MSCs in coculture with immune cells. Pretreatment with hypoxia and inflammatory factors caused UC-MSCs to be elongated but did not affect their viability, proliferation or size. In addition, pretreatment significantly decreased the expression of coagulation-related tissue factors but did not affect the expression of other surface markers. Similarly, mitochondrial function and integrity were retained. Although pretreatment promoted UC-MSC apoptosis and senescence, it increased the expression of genes and proteins related to immune regulation. Pretreatment increased peripheral blood mononuclear cell and natural killer (NK) cell proliferation rates and inhibited NK cell-induced toxicity to varying degrees. In summary, hypoxia and inflammatory factor preconditioning led to higher immunosuppressive effects of MSCs without damaging their biological characteristics.

Dissecting molecular mechanisms underlying ferroptosis in human umbilical cord mesenchymal stem cells: Role of cystathionine γ-lyase/hydrogen sulfide pathway.

Ferroptosis can induce low retention and engraftment after mesenchymal stem cell (MSC) delivery, which is considered a major challenge to the effectiveness of MSC-based pulmonary arterial hypertension (PAH) therapy. Interestingly, the cystathionine γ-lyase (CSE)/hydrogen sulfide (H2S) pathway may contribute to mediating ferroptosis. However, the influence of the CSE/H2S pathway on ferroptosis in human umbilical cord MSCs (HUCMSCs) remains unclear. To clarify whether the effect of HUCMSCs on vascular remodelling in PAH mice is affected by CSE/H2S pathway-mediated ferroptosis, and to investigate the functions of the CSE/H2S pathway in ferroptosis in HUCMSCs and the underlying mechanisms. Erastin and ferrostatin-1 (Fer-1) were used to induce and inhibit ferroptosis, respectively. HUCMSCs were transfected with a vector to overexpress or inhibit expression of CSE. A PAH mouse model was established using 4-wk-old male BALB/c nude mice under hypoxic conditions, and pulmonary pressure and vascular remodelling were measured. The survival of HUCMSCs after delivery was observed by in vivo bioluminescence imaging. Cell viability, iron accumulation, reactive oxygen species production, cystine uptake, and lipid peroxidation in HUCMSCs were tested. Ferroptosis-related proteins and S-sulfhydrated Kelch-like ECH-associating protein 1 (Keap1) were detected by western blot analysis. In vivo, CSE overexpression improved cell survival after erastin-treated HUCMSC delivery in mice with hypoxia-induced PAH. In vitro, CSE overexpression improved H2S production and ferroptosis-related indexes, such as cell viability, iron level, reactive oxygen species production, cystine uptake, lipid peroxidation, mitochondrial membrane density, and ferroptosis-related protein expression, in erastin-treated HUCMSCs. In contrast, in vivo, CSE inhibition decreased cell survival after Fer-1-treated HUCMSC delivery and aggravated vascular remodelling in PAH mice. In vitro, CSE inhibition decreased H2S levels and restored ferroptosis in Fer-1-treated HUCMSCs. Interestingly, upregulation of the CSE/H2S pathway induced Keap1 S-sulfhydration, which contributed to the inhibition of ferroptosis. Regulation of the CSE/H2S pathway in HUCMSCs contributes to the inhibition of ferroptosis and improves the suppressive effect on vascular remodelling in mice with hypoxia-induced PAH. Moreover, the protective effect of the CSE/H2S pathway against ferroptosis in HUCMSCs is mediated via S-sulfhydrated Keap1/nuclear factor erythroid 2-related factor 2 signalling. The present study may provide a novel therapeutic avenue for improving the protective capacity of transplanted MSCs in PAH.

Jagged1 contained in MSC-derived small extracellular vesicles promotes squamous differentiation of cervical cancer by activating NOTCH pathway

PurposeCervical cancer is the fourth most common cancer in women and poses a major threat to women's health, urgently requiring new treatment methods.MethodsThis study first successfully extracted and identified small extracellular vesicles secreted by human umbilical cord-derived mesenchymal stem cells. We studied the effects of MSC-sEV on the squamous differentiation levels of cervical cancer CaSki cells in vitro, and explored the effects of MSC-sEV on the NOTCH pathway, the growth, proliferation, migration abilities and squamous differentiation levels of cervical cancer cells. The roles of MSC-sEV were also verified in human keratinocyte HaCaT cells.ResultsThe results showed that Jagged1 protein on MSC-sEV can bind to NOTCH1 on cervical cancer cells, activate NOTCH signaling, and promote squamous differentiation levels in CaSki cells, thus inhibiting the growth, proliferation and migration abilities of CaSki cells. MSC-sEV can also activate the NOTCH pathway in HaCaT cells, but promote the viability of HaCaT cells.ConclusionMSC-sEV can activate the NOTCH pathway to promote squamous differentiation of CaSki cells and inhibit the growth proliferation and migration abilities of CaSki cells which may be a new mechanism for cervical cancer treatment.

Stem cell therapy with CRISPR/Cas9-mediated MALAT1 delivery modulates miR-142 and rescues wound healing in rats with age-associated diabetic foot ulcers

BackgroundDiabetic foot ulcer (DFU) is a serious diabetes complication, significantly impacting the quality of life, particularly in the elderly. Age-associated DFUs pose additional challenges due to impaired healing mechanisms. Our study aims to explore the role of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) as a miR-142 sponge in repairing diabetic rat foot ulcer tissue under age-associated diabetes, offering a new theoretical basis and therapeutic target for preventing and treating diabetic vascular disease in the elderly. MethodsUsing qPCR, we analyzed MALAT1 and miR-142 expression in EPCs and hUC-MSCs. Targetscan predicted potential interaction targets for MALAT1 and miR-142, confirmed by dual luciferase reporter gene assay. An age-associated diabetic rat model was established using Streptozotocin (STZ) injection. Hypoxia, apoptosis, and angiogenesis-related proteins were assessed through Western Blot. In vitro, miR-142 inhibition and MALAT1 overexpression promoted foot ulcer healing in diabetic rats. ResultsMALAT1 acted as a miR-142 sponge, downregulated in hUC-MSCs under high glucose, relevant to age-associated diabetic foot ulcers. MiR-142 negatively regulated SIRT1 and Nrf2. In vitro experiments demonstrated potential significance for age-related DFU treatment. ConclusionsMALAT1 in human umbilical cord mesenchymal stem cells expedited foot ulcer healing in diabetic rats, particularly in age-associated diabetes, through miR-142 sponge activity. These findings offer insights for novel therapeutic strategies targeting elderly diabetic foot ulcers, emphasizing exogenous stem cell transplantation's potential in effective DFU treatment for the elderly.

Exosomal miR-23a-3p derived from human umbilical cord mesenchymal stem cells promotes remyelination in central nervous system demyelinating diseases by targeting Tbr1/Wnt pathway

Oligodendrocyte precursor cells are present in the adult central nervous system, and their impaired ability to differentiate into myelinating oligodendrocytes can lead to demyelination in patients with multiple sclerosis, accompanied by neurological deficits and cognitive impairment. Exosomes, small vesicles released by cells, are known to facilitate intercellular communication by carrying bioactive molecules. In this study, we utilized exosomes derived from human umbilical cord mesenchymal stem cells (HUMSCs-Exos). We performed sequencing and bioinformatics analysis of exosome-treated cells to demonstrate that HUMSCs-Exos can stimulate myelin gene expression in oigodendrocyte precursor cells. Functional investigations revealed that HUMSCs-Exos activate the Pi3k/Akt pathway and regulate the Tbr1/Wnt signaling molecules through the transfer of miR-23a-3p, promoting oligodendrocytes differentiation and enhancing the expression of myelin-related proteins. In an experimental autoimmune encephalomyelitis model, treatment with HUMSCs-Exos significantly improved neurological function and facilitated remyelination. This study provides cellular and molecular insights into the use of cell-free exosome therapy for central nervous system demyelination associated with multiple sclerosis, demonstrating its great potential for treating demyelinating and neurodegenerative diseases.

Microfluidic Encapsulation of Exosomes Derived from Lipopolysaccharide-Treated Mesenchymal Stem Cells in Hyaluronic Acid Methacryloyl to Restore Ovarian Function in Mice.

Premature ovarian failure (POF) features an upward incidence nowadays, and the human umbilical cord mesenchymal stem cells (hUC-MSCs)-derived exosomes (MSC-Exos) have shown applied values in the recovery of ovarian function. Here, a novel exosome-encapsulated microcarrier prepared by microfluidic technology for ovarian repair after chemotherapy damage is presented. The exosomes derived from lipopolysaccharide (LPS)-preconditioned hUC-MSCs are encapsulated with hyaluronic acid methacryloyl (HAMA) via microfluidic electrospray, which is named HAMA/MSC-Exos. Attributing to the biocompatibility and semipermeable property of HAMA, the encapsulated exosomes show great viability and controllable release behavior from HAMA. It is demonstrated that in situ transplantation of HAMA/MSC-Exos can rescue ovarian functions of cyclophosphamide-induced ovarian failure in mice by increasing ovarian volume, improving the number of antral follicles and restoring fertility. It is believed that the transplantation of HAMA/MSC-Exos will provide a new concept for the treatment of POF in clinical practice.

Umbilical Cord Mesenchymal Stem Cells Overexpressing Heme Oxygenase-1 Promotes Symptoms Recovery in Cystitis Rats by Alleviating Neuroinflammation.

Interstitial cystitis/bladder pain syndrome (IC/BPS) seriously reduces the patient's quality of life, yet current therapies only provide partial relief. In the spinal dorsal horn (SDH), neuroinflammation plays a pivotal role in the development of IC. Injection of human umbilical cord mesenchymal stem cells (hUMSCs) to reduce inflammation is an effective strategy, and heme oxygenase-1 (HO-1) exhibits anti-nociceptive effect in neuroinflammatory pain. This study aimed to test the therapeutic effects of hUMSCs overexpressing HO-1 on cyclophosphamide-induced cystitis rat model. Cystitis rats were transplanted with altered cells and then assessed for 3 weeks. A series of behavioral measurements would be trial including suprapubic mechanical allodynia, depressive-like behaviors, micturition frequency, and short-term memory function. Additionally, western blot, immunofluorescence staining, and ELISA kit test for anti-inflammation effect. HUMSCs were capable of being transduced to overexpress HO-1. Injection of hUMSCs overexpressing HO-1 was more effective than hUMSCs alone in alleviating behavioral symptoms in rats. Furthermore, hUMSCs overexpressing HO-1 inhibited the activation of glial and TLR4/p65/NLRP3 pathway, decreased the levels of pro-inflammatory cytokines in the SDH region. Surprisingly, it markedly increased anti-inflammatory cytokine IL-10, reduced MDA content, and protected GSH concentrations in local environment. Our results suggest that injecting hUMSCs overexpressing HO-1 intrathecally can significantly promote functional outcomes in cystitis rats by reducing neuroinflammation, at least, partly through downregulating TLR4/p65/NLRP3 signaling pathway in the SDH region. This cell therapy affords a new strategy for IC/BPS treatment.

Exosomal miR-146a-5p derived from human umbilical cord mesenchymal stem cells can alleviate antiphospholipid antibody-induced trophoblast injury and placental dysfunction by regulating the TRAF6/NF-κB axis

Exosomes originating from human umbilical cord mesenchymal stem cells (hucMSC-exos) have become a novel strategy for treating various diseases owing to their ability to regulate intercellular signal communication. However, the potential of hucMSC-exos to improve placental injury in obstetric antiphospholipid syndrome and its underlying mechanism remain unclear. Our objective was to explore the potential application of hucMSC-exos in the treatment of obstetric antiphospholipid syndrome and elucidate its underlying mechanism. In our study, hucMSC-exos ameliorated the functional impairment of trophoblasts caused by antiphospholipid antibodies in vitro and attenuated placental dysfunction in mice with obstetric antiphospholipid syndrome by delivering miR-146a-5p. Exosomal miR-146a-5p suppressed the expression of tumor necrosis factor receptor-associated factor 6 (TRAF6) and inhibited the activation of NF-κB signaling, leading to the down-regulation of IL-1β and IL-18 to rescue inflammation and modulation of Cleaved-CASP3, BAX, and BCL2 to inhibit apoptosis in HTR8/SVneo cells and mice placenta. This study identified the potential molecular basis of how hucMSC-exos improved antiphospholipid antibody-induced placental injury and highlighted the functional importance of the miR-146a-5p/TRAF6 axis in the progression of obstetric antiphospholipid syndrome. More importantly, this study provided a fresh outlook on the promising use of hucMSC-exos as a novel and effective treatment approach in obstetric antiphospholipid syndrome.Graphical

Mesenchymal stem cell secretome ameliorates over-expression of soluble fms-like tyrosine kinase-1 (sFlt-1) and fetal growth restriction (FGR) in animal SLE model

Introduction In the near future, stem cell research may lead to several major therapeutic innovations in medical practice. Secretome, a “by-product” of stem cell line cultures, has many advantages. Its easiness of storage, usage, and fast direct effect are some of those to consider. Fetal growth restriction (FGR) remains one of the significant challenges in maternal-fetal and neonatal medicine. Placentation failure is one of the most profound causal and is often related to increasing sFlt-1 in early pregnancy. This study aimed to investigate hUC-MSC secretome in ameliorating sFlt-1 and how to improve outcomes in preventing FGR in an animal model. Materials and methods Pristane-induced systemic lupus erythematosus (SLE) in a mouse model was used to represent placentation failure and its consequences. Twenty-one mice were randomized into three groups: (I) normal pregnancy, (II) SLE, and (III) SLE with secretome treatment. Pristane was administered in all Groups four weeks prior mating period. Secretome was derived from human umbilical cord mesenchymal stem cells (hUC-MSC) conditioned medium on the 3rd and 4th passage, around day-21 until day-28 from the start of culturing process. Mesenchymal stem cell was characterized using flow cytometry for CD105+, CD90+, and CD73+ surface antigen markers. Immunohistochemistry anlysis by using Remmele’s Immunoreactive Score (IRS) was used to quantify the placental sFlt-1 expression in each group. Birth weight and length were analyzed as the secondary outcome. The number of fetuses obtained was also calculated for pregnancy loss comparison between Groups. Results The administration of secretome of hUC-MSC was found to lower the expression of the placental sFlt-1 significantly in the pristane SLE animal model (10.30 ± 1.40 vs. 4.98 ± 2.57; p < 0.001) to a level seen in normal mouse pregnancies in Group I (3.88 ± 0.49; p = 0.159). Secretome also had a significant effect on preventing fetal growth restriction in the pristane SLE mouse model (birth weight: 354.29 ± 80.76 mg vs. 550 ± 64.03 mg; p < 0.001 and birth length: 14.43 ± 1.27 mm vs. 19.00 ± 1.41 mm), comparable to the birth weight and length of the normal pregnancy in Group I (540.29 ± 75.47 mg and 18.14 ± 1.34 mm, p = 0.808 and = 0.719). Secretome administration also showed a potential action to prevent high number of pregnancy loss as the number of fetuses obtained could be similar to those of mice in the normal pregnant Group (7.71 ± 1.11 vs. 7.86 ± 1.06; p = 0.794). Conclusions Administration of secretome lowers sFlt-1 expression in placenta, improves fetal growth, and prevents pregnancy loss in a mouse SLE model.

Human Umbilical Cord Mesenchymal Stem Cells Repair Endothelial Injury and Dysfunction by Regulating NLRP3 to Inhibit Endothelial Cell Pyroptosis in Kawasaki Disease.

Vascular endothelial inflammation and endothelial dysfunction are the main causes of endothelial injury in Kawasaki disease (KD). Human umbilical cord-derived mesenchymal stem cells (Huc-MSCs) have multiple functions in immune regulation. This study examined whether Huc-MSCs inhibited endothelial inflammation and improved endothelial function in KD through constructing cell and in vivo animal KD vasculitis models. The pyroptosis factor NOD-like receptor protein 3 (NLRP3) was involved in the inflammatory process in the acute phase of KD. After tail vein injection of Huc-MSCs, inflammatory cell infiltration and the expression of pyroptosis-related proteins in the LCWE-induced KD mouse vasculitis model were significantly reduced. In vitro, NLRP3-dependent pyroptosis successfully induced human umbilical vein endothelial cell (HUVEC) damage. Huc-MSCs effectively increased the abilities of impaired HUVECs to proliferate, migrate, invade, and form vessel-like tubes, while inhibiting their apoptosis, suggesting that Huc-MSCs can reduce inflammation and improve vascular endothelial function by inhibiting the NLRP3-dependent pyroptosis pathway in KD, providing a possibility and novel target for KD endothelial injury and dysfunction.

Mitochondrial transplantation reduces lower limb ischemia-reperfusion injury by increasing skeletal muscle energy and adipocyte browning

Recent studies have shown that mitochondrial transplantation can repair lower limb IRI, but the underlying mechanism of the repair effect remains unclear. In this study, we found that in addition to being taken up by skeletal muscle cells, human umbilical cord mesenchymal stem cells (hMSCs)-derived mitochondria were also taken up by adipocytes, which was accompanied by an increase in optic atrophy 1 (OPA1) and uncoupling protein 1. Transplantation of hMSCs-derived mitochondria could not only supplement the original damaged mitochondrial function of skeletal muscle, but also promote adipocyte browning by increasing the expression of OPA1. In this process, mitochondrial transplantation can reduce cell apoptosis and repair muscle tissue, which promotes the recovery of motor function invivo. To the best of our knowledge, there is no study on the therapeutic mechanism of mitochondrial transplantation from this perspective, which could provide a theoretical basis.

Exosomes derived from uMSCs promote hair regrowth in alopecia areata through accelerating human hair follicular keratinocyte proliferation and migration.

Alopecia areata (AA) is a complex genetic disease that results in hair loss due to an autoimmune-mediated attack on the hair follicle. Mesenchymal stem cells (MSCs) have great potential to induce hair regeneration due to their strong secretion ability and multidirectional differentiation. Recent studies have revealed that the therapeutic potential of MSCs comes from their secretion ability, which can produce large amounts of bioactive substances and regulate the key physiological functions of subjects. The secretion products of MSCs, such as vesicles, exosomes, and conditioned media, have significant advantages in preparing of biological products derived from stem cells. Human umbilical cord mesenchymal stem cells (uMSCs) are the best choice for exosome production. uMSCs are obtained from the human umbilical cord. The umbilical cord is easy to obtain, and the efficiency of uMSCs isolation and culture higher than that of obtaining MSCs from bone marrow or adipose tissue. In this study, we investigated the effects of exosomes released from uMSCs in AA mice. In summary, due to easy isolation and cultivation, simple preparation, and convenient storage, it is possible to obtain uMSCs, or uMSCs exosomes for research and clinical treatment.

A repeat-dose toxicity study of human umbilical cord mesenchymal stem cells in NOG mice by intravenous injection

ABSTRACT Background Stem cell-based therapies have demonstrated great potential in several clinical trials. However, safety data on stem cell application remain inadequate. This study evaluated the toxicity of human umbilical cord mesenchymal stem cells (hUC-MSCs) in NOD/Shi-scid/IL-2 Rγnull (NOG) mice. Research design and methods Mice were administered hUC-MSCs intravenously at doses of 3.5 × 106 cells/kg and 3.5 × 107 cells/kg. Toxicity was assessed by clinical observation, behavioral evaluation, pathology, organ weight, and histopathology. We determined the distribution of hUC-MSCs using a validated qPCR method and colonization using immunohistochemistry. Results No significant abnormal effects on clinical responses, body weight, or food intake were observed in the mice, except for two in the high-dose group that died during the last administration. Mouse activity in the high-dose group decreased 6 h after the first administration. Terminal examination revealed dose-dependent changes in hematology. The mice in the high-dose group displayed pulmonary artery wall plaques and mild alveolar wall microthrombi. hUC-MSCs colonized primarily the lung tissues and were largely distributed there 24 h after the final administration. Conclusions The no observed adverse effect level for intravenous administration of hUC-MSCs in NOG mice over a period of 3 w was 3.5 × 106 cells/kg.

A Response to Article "Effectiveness of Secretome from Human Umbilical Cord Mesenchymal Stem Cells in Gel (10% SM-hUCMSC Gel) for Chronic Wounds (Diabetic and Trophic Ulcer) - Phase 2 Clinical Trial" [Letter

A Response to Article "Effectiveness of Secretome from Human Umbilical Cord Mesenchymal Stem Cells in Gel (10% SM-hUCMSC Gel) for Chronic Wounds (Diabetic and Trophic Ulcer) - Phase 2 Clinical Trial" [Letter

Novel 3D-printing bilayer GelMA-based hydrogel containing BP, β-TCP and exosomes for cartilage–bone integrated repair

The integrated repair of cartilage and bone involves the migration and differentiation of cells, which has always been a difficult problem to be solved. We utilize the natural biomaterial gelatin to construct gelatin methacryloyl (GelMA), a hydrogel scaffold with high cell affinity. GelMA is mixed with different components to print a bi-layer porous hydrogel scaffold with different modulus and composition in upper and lower layers through three-dimensional (3D) printing technology. The upper scaffold adds black phosphorus (BP) and human umbilical cord mesenchymal stem cells (hUMSCs) exosomes (exos) in GelMA, which has a relatively lower elastic modulus and is conducive to the differentiation of BMSCs into cartilage. In the lower scaffold, in addition to BP and hUMSCs exos, β-tricalcium phosphate (β-TCP), which has osteoconductive and osteoinductive effects, is added to GelMA. The addition of β-TCP significantly enhances the elastic modulus of the hydrogel scaffold, which is conducive to the osteogenic differentiation of bone marrow mesenchymal stem cells(BMSCs). In vitro experiments have confirmed that the bi-layer scaffolds can promote osteogenesis and chondrogenic differentiation respectively. And in the rabbit cartilage–bone injury model, MRI and micro-CT results show that the 3D printed bi-layer GelMA composite scaffold has a repair effect close to normal tissue.

PLGA nanoparticles engineering extracellular vesicles from human umbilical cord mesenchymal stem cells ameliorates polyethylene particles induced periprosthetic osteolysis

The wear particle-induced dissolution of bone around implants is a significant pathological factor in aseptic loosening, and controlling prosthetic aseptic loosening holds crucial social significance. While human umbilical cord mesenchymal stem cell-derived exosomes (HucMSCs-Exos, Exos) have been found to effectively promote osteogenesis and angiogenesis, their role in periprosthetic osteolysis remains unexplored. To enhance their in vivo application, we engineered HucMSCs-Exos-encapsulated poly lactic-co-glycolic acid (PLGA) nanoparticles (PLGA-Exos). In our study, we demonstrate that PLGA-Exos stimulate osteogenic differentiation while inhibiting the generation of reactive oxygen species (ROS) and subsequent osteoclast differentiation in vitro. In vivo imaging revealed that PLGA-Exos released exosomes slowly and maintained a therapeutic concentration. Our in vivo experiments demonstrated that PLGA-Exos effectively suppressed osteolysis induced by polyethylene particles. These findings suggest that PLGA-Exos hold potential as a therapeutic approach for the prevention and treatment of periprosthetic osteolysis. Furthermore, they provide novel insights for the clinical management of osteolysis.

Biodistribution-based Administration of cGMP-compliant Human Umbilical Cord Mesenchymal Stem Cells Affects the Therapeutic Effect of Wound Healing.

Although mesenchymal stem cells (MSCs) are used as therapeutic agents for skin injury therapy, few studies have reported the effects of dosing duration and delivery frequency on wound healing. In addition, before the clinical application of MSCs, it is important to assess whether their usage might influence tumor occurrence. We described the metabolic patterns of subcutaneous injection of hUC-MSCs using fluorescence tracing and qPCR methods and applied them to the development of drug delivery strategies for promoting wound healing. (i) We developed cGMP-compliant hUC-MSC products with critical quality control points for wound healing; (ii) The products did not possess any tumorigenic or tumor-promoting/inhibiting ability in vivo; (iii) Fluorescence tracing and qPCR analyses showed that the subcutaneous application of hUC-MSCs did not result in safety-relevant biodistribution or ectopic migration; (iv) Reinjecting hUC-MSCs after significant consumption significantly improved reepithelialization and dermal regeneration. Our findings provided a reference for controlling the quality of MSC products used for wound healing and highlighted the importance of delivery time and frequency for designing in vivo therapeutic studies.