Umbilical Cord Matrix Stem Cells Research Articles

Platycodi radix aqueous extract salvages doxorubicin-induced senescence by mitochondrial reactive oxygen speciesreduction in umbilical cord matrix stem cells.

Platycodi radix is a widely used herbal medicine that contains numerous phytochemicals beneficial to health. The health and biological benefits of P. radix have been found across various diseases. The utilization of umbilical cord stromal stem cells, derived from Wharton's jelly of the human umbilical cord, has emerged as a promising approach for treating degenerative diseases. Nevertheless, growing evidence indicates that the function of stem cells declines with age, thereby limiting their regenerative capacity. The primary objective in this study is to investigate the beneficial effects of P. radix in senescent stem cells. We conducted experiments to showcase that diminished levels of Lamin B1 and Sox-2, along with an elevation in p21, which serve as indicative markers for the senescent stem cells. Our findings revealed the loss of Lamin B1 and Sox-2, coupled with an increase in p21, in umbilical cord stromal stem cells subjected to a low-dose (0.1 μM) doxorubicin (Dox) stimulation. However, P. radix restored the Dox-damage in the umbilical cord stromal stem cells. P. radix reversed the senescent conditions when the umbilical cord stromal stem cells exposed to Dox-induced reactive oxygen species (ROS) and mitochondrial membrane potential are significantly changed. In Dox-challenged aged umbilical cord stromal stem cells, P. radix reduced senescence, increased longevity, prevented mitochondrial dysfunction and ROS and protected against senescence-associated apoptosis. This study suggests that P. radix might be as a therapeutic and rescue agent for the aging effect in stem cells. Inhibition of cell death, mitochondrial dysfunction and aging-associated ROS with P. radix provides additional insights into the underlying molecular mechanisms.

Utilization of a Commercial 3D Printer for the Construction of a Bio-Hybrid Device Based on Bioink and Adult Human Mesenchymal Cells

The biofabrication of three-dimensional scaffolds using 3D printers and cell-containing bioinks is very promising. A wide range of materials and bioink compositions are being created and tested for cell viability and printability in order to satisfy the requirements of a bioink. This methodology has not still achieved technological maturity, and the actual costs mean that they are often inaccessible for researchers, consequently lowering the development and extending the required times. This research aims to apply this methodology on a laboratory scale by re-adapting a commercial 3D printer, consequently lowering the costs and energy impacts, and, at the same time, ensuring a level of accuracy extremely close to the currently adopted devices and, more in general, suitable for the scopes of the research. To accomplish this, we assembled a biomimetic scaffold made of human Umbilical Cord Matrix Stem Cells (hUCMS), cellulose, and alginate. Various molds were used to produce 3D scaffolds of different sizes. After bioprinting, cell viability was analyzed using ethidium bromide and fluorescein diacetate, and a histological stain was used to evaluate cell and bioink morphology. All of the examined bioinks had a uniform final 3D structure and were stable, easily printable, and procedure-adapted. Up until 21 days of culture, the bioinks remained unaltered and were simple to manipulate. After 7 and 21 days of cell culture, the hUCMS in the cellulose/alginate-based bioinks exhibited cell viabilities of 95% and 85%, respectively. The cells did not present with a fibroblast-like shape but appeared to be round-shaped and homogeneously distributed in the 3D structure. Biomimetic bioink, which is based on cellulose and alginate, is an appropriate hydrogel for 3D bioprinting. This preliminary work illustrated the potential use of these two biomaterials for the 3D bioprinting of mesenchymal stem cells.

Chorionic Villus-Derived Mesenchymal Stem Cells Induce E3 Ligase TRIM72 Expression and Regulate Cell Behaviors Through Ubiquitination of p53 in Trophoblasts

Background: It was designed to investigate whether umbilical cord matrix stem cells (CVMSC) could affect the functionality of trophoblasts to prevent preeclampsia. Methods: In this study, CVMSC-derived exosomes were isolated; its effect on trophoblasts was investigated based on the CCK8 assay, migration assay, and apoptosis detection. And the underlying mechanism of this effect was investigated using mRNA sequencing, western blot, co-immunoprecipitation, luciferase report assay, and ubiquitination assay. Findings: The results showed that CVMSC-derived exosomes promoted migration and proliferation of trophoblasts, and also reduced cell apoptosis. mRNA sequencing confirmed that after treatment of CVMSC-derived exosomes, TRIM72 expression was upregulated and P53 expression was downregulated, both significantly in trophoblasts. Subsequent study confirmed that TRM72 could directly interact with P53 and promoted P53 ubiquitination and proteasomal degradation, reducing apoptosis rate and elevating proliferation and migration in trophoblasts. Interpretation: Our study confirmed that CVMSC-derived exosomes promoted trophoblast migration and proliferation by upregulating TRIM72 expression, and subsequently advanced P53 ubiquitination and proteasomal degradation. Funding Statement: This study received no specific grant from public funding agencies, commercial, or not-for-profit sectors. Declaration of Interests: All authors declare there is no competing interest. Ethics Approval Statement: This study was approved by the Ethics Committee of the Affiliated Hospital of Qingdao University.

Evaluating the effect of transplanting umbilical cord matrix stem cells on ischemic tolerance in an animal model of stroke

ABSTRACT Objective Stroke, a cerebrovascular disease, has been introduced as the second cause of death and physical disability in the world. Recently, cell-based therapy has been considered by the scientific community as a promising strategy for reducing ischemic damages. The stem cells of the umbilical cord release growth and neurotrophic factors. The remarkable properties of these cells are the reason why they were selected as a potential candidate in the present research. Methods In this study, the impact of transplanting umbilical cord stem cells on injuries resulting from ischemia was investigated. The male rats were categorized into three major. Using stereotaxic surgery, stem cells were injected to the right striatum of the brain. One week after transplantation, cerebral ischemic induction surgery was performed. The rats in the transplantation + ischemia group were separately divided into distinct sub-groups to explore the score of the neurological deficits, infarction volume, integrity of the blood-brain barrier, and brain edema. Results In this study, a significant decrease was observed in the neurological deficits of the transplantation + ischemia group compared with those of the control group. Similarly, the volume of infarction, the permeability of the blood-brain barrier, and edema were significantly reduced in the transplantation + ischemia group in comparison with those of the control group. Conclusion The pretreatment of the transplanted umbilical cord stem cells in the striatum of ischemic rats possibly leads to restorative events, exerting a decreasing effect on cell death. Subsequently, these events may improve the motor ability and reduce ischemic injuries.

Umbilical cord-matrix stem cells induce the functional restoration of vascular endothelial cells and enhance skin wound healing in diabetic mice via the polarized macrophages

BackgroundChronic nonhealing wounds represent one of the most common complications of diabetes and require advanced treatment strategies. Increasing evidence supports the important role of mesenchymal stem cells in diabetic wound healing; however, the underlying mechanism remains unclear. Here, we explored the effects of umbilical cord-matrix stem cells (UCMSCs) on diabetic wound healing and the underlying mechanism.MethodsUCMSCs or conditioned medium (UCMSC-CM) were injected into the cutaneous wounds of streptozotocin-induced diabetic mice. The effects of this treatment on macrophages and diabetic vascular endothelial cells were investigated in vivo and in vitro.ResultsOur results reveal that UCMSCs or UCMSC-CM accelerated wound healing by enhancing angiogenesis. The number of host macrophages recruited to the wound tissue by local infusion of UCMSCs was greater than that recruited by fibroblast transplantation or control. The frequency of M2 macrophages was increased by UCMSC transplantation or UCMSC-CM injection, which promoted the expression of cytokines derived from M2 macrophages. Furthermore, when cocultured with UCMSCs or UCMSC-CM, lipopolysaccharide-induced macrophages acquired an anti-inflammatory M2 phenotype characterized by the increased secretion of the cytokines interleukin (IL)-10 and vascular endothelial growth factor and the suppressed production of tumor necrosis factor-α and IL-6. UCMSC-CM-activated macrophages significantly enhanced diabetic vascular endothelial cell functions, including angiogenesis, migration, and chemotaxis. Moreover, the action of UCMSC-CM on macrophages or vascular endothelial cells was abrogated by the administration of neutralizing antibodies against prostaglandin E2 (PGE2) or by the inhibition of PGE2 secretion from UCMSCs.ConclusionsOur findings demonstrate that UCMSCs can induce the functional restoration of vascular endothelial cells via the remodeling of macrophage phenotypes, which might contribute to the marked acceleration of wound healing in diabetic mice.Graphical

Study on Umbilical Cord-Matrix Stem Cells Transplantation for Treatment of Acute Traumatic Brain Injury in Rats.

To evaluate the effect of umbilical cord derived mesenchymal stem cells (UC-MSCs) transplantation on traumatic brain injury (TBI). UC-MSCs were isolated from human umbilical cord and TBI rat model was constructed. 30 male SD rats were randomly divided into 3 groups: control group, TBI group and MSCs transplantation group. Rats in MSCs group received the injection of a total of 1.5 Ć- 106 MSCs (25 Ī¼l) via ventricle at operated ventricular coordinates (0 at bregma, 1.5 mm at lateral, 1.1 mm at behind, 4.5 mm in depth). 80% confluence of cells was formed from tissue at day 10 and the amount of CD90, CD73, CD105 positive cells increased correspondingly. In TBI model, clear hyperemia, edema and obvious infiltration of inflammatory cells in brain tissue were found. However, the manifestations were alleviated after the treatment of MSCs. In MSCs group, GFP in the brain tissue and the area around the vessels were found after the injection, while the expression levels of micro-vessel density (MVD), brain-derived neurotrophic factor (BDNF) and glial fibrillary acidic protein (GFAP) were elevated. UC-MSCs transplantation for treatment of acute TBI could effectively reduce the injury and improve the vascular reconstruction.

Human Umbilical Cord Matrix Stem Cells Reverse Oxidative Stress-Induced Cell Death and Ameliorate Motor Function and Striatal Atrophy in Rat Model of Huntington Disease.

Huntington disease (HD) is an inherited disorder hallmarked by progressive deterioration of specific neurons, followed by movement and cognitive anomalies. Cell therapy approaches in neurodegenerative conditions have concentrated on the replenishment of lost/dying neurons with functional ones. Multipotent mesenchymal stem cells (MSCs) have been represented as a potential remedy for HD. In this study, we evaluated the in vitro and in vivo efficacy of umbilical cord matrix stem cells (UCMSCs) and their paracrine effect against oxidative stress with a specific focus on HD. To this end, UCMSCs were isolated, immunophenotypically characterized by the positive expression of MSC markers, and exhibited multilineage potentiality. Besides, synthesis of neurotrophic factors of GDNF and VEGF by UCMSC was confirmed. Initially, PC12 cells were exposed to superoxide in the presence of conditioned media (CM) collected from UCMSC (UCMSC-CM) and cell viability plus neuritogenesis were measured. Next, bilateral striatal transplantation of UCMSC in 3-nitropropionic acid (3-NP) lesioned rat models was conducted, and 1month later, post-graft analysis was performed. According to our in vitro results, CM of UCMSC protected PC12 cells against oxidative stress and considerably enhanced cell viability and neurite outgrowth. On the other hand, transplanted UCMSC survived, decreased gliosis, and ameliorated motor coordination and muscle activity, along with an increase in striatal volume as well as in dendritic length of the striatum in HD rats. Collectively, our findings imply that UCMSCs provide an enriched platform by largely their paracrine factors, which downgrades the unfavorable effects of oxidative stress.

Upregulation of sodium taurocholate cotransporter polypeptide during hepatogenic differentiation of umbilical cord matrix mesenchymal stem cells facilitates hepatitis B entry

BackgroundHepatitis B virus (HBV) carriers worldwide number approximately 240 million people and around 780,000 people die every year from HBV infection. HBV entry and uptake are functionally linked to the presence of the human sodium-taurocholate cotransporting peptide (hNTCP) receptor. Recently, our group demonstrated that human umbilical cord matrix stem cells (UCMSCs) become susceptible to HBV after in-vitro hepatogenic differentiation (D-UCMSCs).MethodsIn the present study, we examined the involvement of hNTCP in governing D-UCMSC susceptibility to HBV infection by characterizing the modulation of this transporter expression during hepatogenic differentiation and by appreciating the inhibition of its activity on infection efficacy.ResultsWe show here that in-vitro hepatogenic differentiation upregulated hNTCP mRNA and protein expression as well as its activity in D-UCMSCs. Pre-treatment of D-UCMSCs with taurocholate, a specific NTCP substrate, blocked their infection by HBV which supports the crucial involvement of this transporter in the early steps of the virus entry.ConclusionAltogether, our data support the usefulness of D-UCMSCs as a unique human and non-transformed in-vitro model to study the early stages of HBV infection thanks to its ability to endogenously regulate the expression of hNTCP.

Design of a nanocomposite substrate inducing adult stem cell assembly and progression toward an Epiblast-like or Primitive Endoderm-like phenotype via mechanotransduction.

This work shows that the active interaction between human umbilical cord matrix stem cells and Poly (l-lactide)acid (PLLA) and PLLA/Multi Walled Carbon Nanotubes (MWCNTs) nanocomposite films results in the stem cell assembly as a spheroid conformation and affects the stem cell fate transition. We demonstrated that spheroids directly respond to a tunable surface and the bulk properties (electric, dielectric and thermal) of plain and nanocomposite PLLA films by triggering a mechanotransduction axis. This stepwise process starts from tethering of the cells' focal adhesion proteins to the surface, together with the adherens junctions between cells. Both complexes transmit traction forces to F-Actin stress fibres that link Filamin-A and Myosin-IIA proteins, generating a biological scaffold, with increased stiffening conformation from PLLA to PLLA/MWCNTs, and enable the nucleoskeleton proteins to boost chromatin reprogramming processes. Herein, the opposite expression of NANOG and GATA6 transcription factors, together with other lineage specification related proteins, steer spheroids toward an Epiblast-like or Primitive Endoderm-like lineage commitment, depending on the absence or presence of 1wt% MWCNTs, respectively. This work represents a pioneering effort to create a stem cell/material interface that can model the stem cell fate transition under growth culture conditions.

Significance of soluble growth factors in the chondrogenic response of human umbilical cord matrix stem cells in a porous three dimensional scaffold

Stem cell based tissue engineering has emerged as a promising strategy for articular cartilage regeneration. Foetal derived mesenchymal stem cells (MSCs) with their ease of availability, pluripotency and high expansion potential have been demonstrated to be an attractive cell source over adult MSCs. However, there is a need for optimisation of chondrogenic signals to direct the differentiation of these multipotent MSCs to chondrogenic lineage. In this study we have demonstrated the in vitro chondrogenesis of human umbilical cord matrix MSCs in three dimensional PVA-PCL (polyvinyl alcohol-polycaprolactone) scaffolds in the presence of the individual growth factors TGFβ1, TGFβ3, IGF, BMP2 and their combination with BMP2. Gene expression, histology and immunohistology were evaluated after 28d culture. The induced cells showed the feature of chondrocytes in their morphology and expression of typical chondrogenic extracellular matrix molecules. Moreover, the real-time PCR assay has shown the expression of gene markers of chondrogenesis, SOX9, collagen type II and aggrecan. The expression of collagen type I and collagen type X was also evaluated. This study has demonstrated the successful chondrogenic induction of human umbilical cord MSCs in 3D scaffolds. Interestingly, the growth factor combination of TGF-β3 and BMP-2 was found to be more effective for chondrogenesis as shown by the real-time PCR studies. The findings of this study suggest the importance of using growth factor combinations for successful chondrogenic differentiation of umbilical cord MSCs.

Human Umbilical Cord Matrix Stem Cells Maintain Multilineage Differentiation Abilities and Do Not Transform during Long-Term Culture

Umbilical cord matrix stem cells (UCMSC) have generated great interest in various therapeutic approaches, including liver regeneration. This article aims to analyze the specific characteristics and the potential occurrence of premalignant alterations of UCMSC during long-term expansion, which are important issues for clinical applications. UCMSC were isolated from the umbilical cord of 14 full-term newborns and expanded in vitro until senescence. We examined the long-term growth potential, senescence characteristics, immunophenotype and multilineage differentiation capacity of these cells. In addition, their genetic stability was assessed through karyotyping, telomerase maintenance mechanisms and analysis of expression and functionality of cell cycle regulation genes. The tumorigenic potential was also studied in immunocompromised mice. In vitro, UCMSC reached up to 33.7±2.1 cumulative population doublings before entering replicative senescence. Their immunophenotype and differentiation potential, notably into hepatocyte-like cells, remained stable over time. Cytogenetic analyses did not reveal any chromosomal abnormality and the expression of oncogenes was not induced. Telomere maintenance mechanisms were not activated. Just as UCMSC lacked transformed features in vitro, they could not give rise to tumors in vivo. UCMSC could be expanded in long-term cultures while maintaining stable genetic features and endodermal differentiation potential. UCMSC therefore represent safe candidates for liver regenerative medicine.

Naïve rat umbilical cord matrix stem cells significantly attenuate mammary tumor growth through modulation of endogenous immune responses

Background aimsUn-engineered human and rat umbilical cord matrix stem cells (UCMSCs) attenuate growth of several types of tumors in mice and rats. However, the mechanism by which UCMSCs attenuate tumor growth has not been studied rigorously. MethodsThe possible mechanisms of tumor growth attenuation by rat UCMSCs were studied using orthotopic Mat B III rat mammary tumor grafts in female F344 rats. Tumor-infiltrating leukocytes were identified and quantified by immunohistochemistry analysis. Potential cytokines involved in lymphocyte infiltration in the tumors were determined by microarray and Western blot analysis. The Boyden chamber migration assay was performed for the functional analysis of identified cytokines. ResultsRat UCMSCs markedly attenuated tumor growth; this attenuation was accompanied by considerable lymphocyte infiltration. Immunohistochemistry analysis revealed that most infiltrating lymphocytes in the rat UCMSC-treated tumors were CD3+ T cells. In addition, treatment with rat UCMSCs significantly increased infiltration of CD8+ and CD4+ T cells and natural killer (NK) cells throughout tumor tissue. CD68+ monocytes/macrophages and Foxp3+ regulatory T cells were scarcely observed, only in the tumors of the phosphate-buffered saline control group. Microarray analysis of rat UCMSCs demonstrated that monocyte chemotactic protein-1 is involved in rat UCMSC-induced lymphocyte infiltration in the tumor tissues. ConclusionsThese results suggest that naïve rat UCMSCs attenuated mammary tumor growth at least in part by enhancing host anti-tumor immune responses. Naïve UCMSCs can be used as powerful therapeutic cells for breast cancer treatment, and monocyte chemotactic protein-1 may be a key molecule to enhance the effect of UCMSCs at the tumor site.

The Therapeutic Potential of Umbilical Cord Mesenchymal Stem Cells in Mice Premature Ovarian Failure

Mesenchymal stem cells, which are poorly immunogenic and have potent immunosuppressive activities, have emerged as promising cellular therapeutics for the treatment of several diseases. Mesenchymal-like cells derived from Wharton's Jelly, called umbilical cord matrix stem cells (UCMSCs), reportedly secrete a variety of cytokines and growth factors, acting as trophic suppliers. Here, we used UCMSCs to treat premature ovarian failure (POF). Ovarian function was evaluated by ovulation and the number of follicles. Apoptosis of the granulosa cells (GC) was analyzed by TUNEL staining. We found that after transplantation of the UCMSCs, apoptosis of cumulus cells in the ovarian damage model was reduced and the function of the ovary had been recovered. The sex hormone level was significantly elevated in mice treated with UCMSCs. The number of follicles in the treated group was higher than in the control group. Our results demonstrate that UCMSCs can effectively restore ovary functionality and reduce apoptosis of granulosa cells. We compared the RNA expression of the UCMSCs treated group with the POF model and wild-type control group and found that the UCMSC group is most similar to the wild-type group. Our experiments provide new information regarding the treatment of ovarian function failure.

Differentiated umbilical cord matrix stem cells as a newin vitromodel to study early events during hepatitis B virus infection

The role of cell differentiation state on hepatitis B virus (HBV) replication has been well demonstrated, whereas how it determines cell susceptibility to HBV entry is far less understood. We previously showed that umbilical cord matrix stem cells (UCMSC) can be differentiated towards hepatocyte-like cells in vitro. In this study we infected undifferentiated (UD-) and differentiated (D-) UCMSCs with HBV and studied the infection kinetics, comparing them to primary human hepatocytes (PHHs). UD-UCMSCs, although permissive to viral binding, had a very limited uptake capacity, whereas D-UCMSCs showed binding and uptake capabilities similar to PHHs. Likewise, asialoglycoprotein receptor (ASGPR) was up-regulated in UCMSCs upon differentiation. In D-UCMSCs, a dose-dependent inhibition of HBV binding and uptake was observed when ASGPR was saturated with known specific ligands. Subsequent viral replication was shown in D-UCMSCs but not in UD-UCMSCs. Susceptibility of UCMSCs to viral replication correlated with the degree of differentiation. Replication efficiency was low compared to PHHs, but was confirmed by (1) a dose-dependent inhibition by specific antiviral treatment using tenofovir; (2) the increase of viral RNAs along time; (3) de novo synthesis of viral proteins; and (4) secretion of infectious viral progeny. UCMSCs become supportive of the entire HBV life cycle upon in vitro hepatic differentiation. Despite low replication efficiency, D-UCMSCs proved to be fully capable of HBV uptake. Overall, UCMSCs are a unique human, easily available, nontransformed, in vitro model of HBV infection that could prove useful to study early infection events and the role of the cell differentiation state on such events.

Human Umbilical Cord Matrix Stem Cells Efficiently Rescue Acute Liver Failure Through Paracrine Effects Rather than Hepatic Differentiation

There is increasing evidence that mesenchymal stem cells (MSCs) derived from different tissues could act as an alternative source of mature hepatocytes for treatment of acute liver failure (ALF). Human umbilical cord matrix stem cells (hUCMSCs) represent a novel source of MSCs. We examined the therapeutic potential and the different mechanisms of hUCMSCs by their transplantation into nonobese diabetic severe combined-immunodeficient (NOD-SCID) mice with carbon tetrachloride (CCl(4))-induced ALF in comparison to adult human hepatocytes (AHHs). The characteristics of isolated hUCMSCs were determined from MSCs and hepatocyte marker expression, hepatic function, and differentiation. Native hUCMSCs constitutively expressed some hepatic markers, though weaker hepatocyte-specific functions were observed when compared to AHHs. When native hUCMSCs or AHHs were transplanted into livers of NOD-SCID mice with ALF induced by CCl(4), both hUCMSCs and AHHs provided a significant survival benefit and prevented the release of liver injury biomarkers. hUCMSCs were found to engraft within the recipient liver and differentiated into functional hepatocytes, whereas the HepPar1-/albumin (ALB)-positive cells of the hUCMSC group were less than the AHH group in the recipient liver. Higher values of human ALB in the serum of mice-transplanted AHHs were determined in comparison with levels in mice-transplanted hUCMSCs. The analysis of mouse serum cytokine levels showed that hUCMSC transplantation was even more effective than treatment with AHHs and successfully downregulated the systemic inflammatory cytokines such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-6, IL-10, and IL-1 receptor antagonist (IL-1RA). Furthermore, paracrine effects produced by hUCMSCs were identified by indirect coculture with damaged mouse hepatocytes (MHs) induced by CCl(4). Coculture with hUCMSCs significantly increased the viability, ALB secretion of damaged MHs, and greatly enhanced the regeneration of MHs in vitro when compared with AHHs. These data suggest that direct transplantation of native hUCMSCs can rescue ALF and repopulate livers of mice through paracrine effects to stimulate endogenous liver regeneration rather than hepatic differentiation for compensated liver function, which is the primary effect of AHHs. Thus, hUCMSCs can be a potential alternative source of AHHs for cell therapy of ALF and eliminate the shortage of hepatocytes.

Confocal Imaging of Trans‐epithelial Trafficking by Immune and Umbilical Cord Stem Cells in the Neonatal Porcine Intestine

Maternal colostral leucocytes (CL) and peripheral blood mononuclear cells (PBMC) enter the neonatal circulation after ingestion in pigs and cattle. Porcine umbilical cord matrix stem cells (PUCs) are relatively non-immunogenic after initial allogeneic transplantation. Using intestinal explant cultures incubated with labelled cells and confocal microscopy, we demonstrated trans-epithelial trafficking of exogenous CL, PBMC and PUCs below the luminal surface after 72 h of culture. We orally administered PBMC and PUCs to pre-colostral neonatal pigs and tracked their location 8 or 24 h later. Both PBMC and PUCs were found in the intestinal wall of all samples. Exposure to 25% of acellular colostrum had no detected effect on trafficking. Labelled PUCs and PBMC were detected on the surface of the epithelium and in the lamina propria 8 h post-treatment and PBMC were also in the superficial submucosa. At 24 h, PUCs and PBMC were observed on the surface of the epithelium, in the lamina propria, superficial submucosa and deep submucosa. Our findings show the potential of PUCs for allogeneic engraftment in the neonatal intestine and may lead to cell-based delivery of therapeutics.

Umbilical cord matrix stem cells trophic ability and use as a drug delivery vehicle for treatment of melanomas

Melanoma is caused by uncontrolled growth of melanocytes, which can lead to a progressive form of malignant melanoma with limited treatment options. Stem cells have previously demonstrated a trophic ability to melanoma, which could be used as an anti‐cancer delivery system. Interferon‐β (IFN‐β) has been used as an anti‐cancer drug in previous studies. Our aim was to use umbilical cord matrix stem cells (UCMSC) loaded with IFN‐β (UCMSC‐IFN‐β) as drug delivery vehicles for melanoma treatment. To investigate the trophic ability of UCMSC towards B16F10 melanoma cells, we plated B16F10 melanoma cells at increasing concentrations in the bottom of a transwell plate and UCMSC's plated in the top of transwells. After 24 hours, the number of UCMSC's showing trophic ability was counted. All the experiments were replicated three times. To investigate the anti‐cancer ability of UCMSC‐IFN‐β on B16F10 melanoma cells, we plated B16F10 melanoma cells at increasing concentrations in the bottom of a transwell plate. UCMSC and UCMSC‐IFN‐β were then plated in the top of the transwells. After 48 hours, the number of B16F10 melanoma cells both alive and dead was counted. All the experiments were replicated three times. This in vitro study shows that as melanoma cells concentration increased, the amount of UCMSC migration increased as well. The second study showed that wells with UCMSC‐IFN‐β had higher amounts of dead B16F10 melanoma cells as compared to the control wells with UCMSC. These results indicate the trophic ability of UCMSC's and the use as a drug delivery vehicle through the anti‐cancer ability of UCMSC‐IFN‐β.Grant Funding Source : A.T. Still University Graduate Program

Local Transplant of Human Umbilical Cord Matrix Stem Cells Improves Skin Flap Survival in a Mouse Model

A skin flap is a piece of skin that has its own blood supply, which is useful to repair large skin defects and deep wounds in plastic surgery. However, partial skin flap necrosis usually occurred. Bone marrow mesenchymal stem cells (BM MSCs) are effective in improving the ischemic flap survival, but their clinical application is restricted by their limited source. Human umbilical cord matrix stem (HUCMS) cells are easily isolated in a large number, compared to BM MSCs. In this study, we evaluated the therapeutic potential of HUCMS to improve the survival of ischemic skin flap. HUCMS cells were characterized with surface markers, and were labeled with 5-acetylene base-2 'deoxidizing uracil nucleoside (EdU) in vitro. Twenty male immunodeficient BALB/c mice with an epigastric flap were randomly divided into two groups. HUCMS cells or Dulbecco's Modified Eagle Medium (DMEM) were injected into the subcutaneous flap tissues. On the 7th postoperative day, flap survival, capillary density, levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), and EdU-positive cells in the skin flap were examined. Results showed that flap survival rate was higher in the HUCMS cell group (P < 0.05). Capillary density, VEGF level, and bFGF level were higher in the HUCMS cell group (P < 0.05). EdU-labeled HUCMS cells were mainly distributed in the subcutaneous flap tissues. These findings suggest that HUCMS cells can improve the survival of ischemic skin flap by promoting vascularization, which may be attributed to the increased expression of VEGF and bFGF.

Wharton's Jelly Stem Cells as Agents for Cancer Therapy

Stem cell based therapy has significant potential to treat various diseases including primary and metastatic cancers. The umbilical cord matrix stem cells (UCMSC) derived from human umbilical cord Wharton's jelly (also termed WJMSC) have been shown to exhibit low immunogenicity, which potentially negates immune consequences after cytotherapy. The homing ability of human and rat UCMSC to inflammatory tissues, including cancer tissues, further confers upon these cells the potential for targeted cancer therapy. Our previous studies demonstrated that un-engineered human and rat UCMSC significantly attenuated the growth of multiple cancer cell lines in vivo and in vitro through multiple mechanisms. We have also demonstrated that these cells can be engineered to express cytotoxic cytokines before being delivered to the tumor and can be preloaded with nanoparticle payloads and attenuate tumors after homing to them. In this review, intrinsic stem cell-dependent regulation of cancer growth, potential mechanisms involved in this unique biological function, delivery of exogenous anti-cancer agents, and the potential for clinical applications will be discussed.

Identification and Characterization of Unique Tumoricidal Genes in Rat Umbilical Cord Matrix Stem Cells

Rat umbilical cord matrix stem cells (UCMSC) have been shown to exhibit a remarkable ability to control rat mammary adenocarcinoma (Mat B III) cell proliferation both in vivo and in vitro. To study the underlying mechanisms and genes involved in Mat B III growth attenuation, total RNA was extracted from the naive rat UCMSC alone and those cocultured with Mat B III in Transwell culture dishes. Gene expression profiles of naive rat UCMSC alone and those cocultured with Mat B III cells were investigated by microarray analysis using an Illumina RatRef-12 Expression BeadChip. The comparison of gene expression profiles between untreated and cocultured rat UCMSC identified five upregulated candidate genes (follistatin (FST), sulfatase1 (SULF-1), glucose phosphate isomerase (GPI), HtrA serine peptidase (HTRA1), and adipocyte differentiation-related protein (ADRP)) and two downregulated candidate genes (transforming growth factor, beta-induced, 68 kDa (TGFβI) and podoplanin (PDPN)) based upon the following screening criteria: (1) expression of the candidate genes should show at least a 1.5-fold change in rat UCMSC cocultured with Mat B III cells; (2) candidate genes encode secretory proteins; and (3) they encode cell growth-related proteins. Following confirmation of gene expression by real-time PCR, ADRP, SULF-1 and GPI were selected for further analysis. Addition of specific neutralizing antibodies against these three gene products or addition of gene-specific siRNA's individually in cocultures of 1:20 rat UCMSC:Mat B III cells significantly increased cell proliferation, implying that these gene products are produced under the cocultured condition and functionally attenuate cell growth. Immunoprecipitation followed by Western blot analysis demonstrated that these proteins are indeed secreted into the culture medium. Individual overexpression of these three genes in rat UCMSC significantly enhanced UCMSC-dependent inhibition of cell proliferation in coculture. These results suggest that ADRP, SULF-1 and GPI act as tumor suppressor genes, and these genes might be involved in rat UCMSC-dependent growth attenuation of rat mammary tumors.