Mesenchymal stem cells (MSCs) are a type of adult stem cells derived from the mesoderm that possess self-renewal and multi-directional differentiation potential. Their sources primarily include bone marrow, umbilical cord, umbilical cord blood, placenta, dental pulp, adipose tissue, liver, and lungs. MSCs exhibit a fibroblast-like morphology, characterized by their elongated spindle shape and adherence to the growth surface. They are known for their high level of selective paracrine secretion. MSCs possess a strong self-renewal capacity, low immunogenicity, and minimal rejection reactions, which confer advantages in the fields of stem cell transplantation and therapeutic research.
Early research on MSCs primarily focused on bone marrow-derived mesenchymal stem cells (BM-MSCs). However, due to the limited availability of bone marrow sources, difficulties in isolation, high viral infection rates, and the notable decline in the number and proliferation-differentiation capacity of BM-MSCs with age, research shifted towards more abundant sources such as umbilical cord and cord blood. Among these, umbilical cord has gradually emerged as a promising source of MSCs due to its convenient access, ease of long-term cryopreservation, and minimal ethical concerns.Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs), isolated from Wharton's jelly within the umbilical cord, possess characteristics including directed differentiation, promotion of cell proliferation, immune regulation, and reduction of inflammatory responses. Flow cytometry analysis reveals that hUC-MSCs express CD73+, CD105+, and Anti-HLA-ABC, while they do not express CD29, CD34, CD45, or Anti-HLA-DR.hUC-MSCs are capable of secreting a variety of cytokines, exhibiting multi-directional differentiation and immune regulatory abilities. Furthermore, they do not elicit allogeneic rejection reactions, making them a rising star in the field of stem cell therapy today.
Isolation and Extraction of hUC-MSCs
Research has shown that the content of MSCs in mononuclear cells isolated from the amnion and umbilical cord can be as high as 80% to 100%, whereas only 8% of mononuclear cells isolated from umbilical cord blood contain MSCs. The low number of MSCs in umbilical cord blood leads to a success rate of only 7% to 10% in isolating and culturing them successfully, and some studies suggest that these minute quantities are often undetectable, making in vitro expansion challenging.Traditional methods for isolating and purifying hUC-MSCs include tissue adherence culture and enzymatic digestion followed by centrifugation. However, with the deepening of research and understanding of hUC-MSCs, some novel isolation and culture methods have gradually been applied, such as using flow cytometry and immunomagnetic bead sorting. Nevertheless, these two methods require sophisticated equipment and techniques, which do not meet the demands of clinical applications.Furthermore, MSCs subpopulations derived from different individuals and tissue locations exhibit diverse compositions, with varying morphologies and non-uniform expression of surface markers. Currently, there is no single antibody that can definitively identify hUC-MSCs. Therefore, the identification of hUC-MSCs relies on the combination of results from multiple screening methods and their capacity for multi-directional differentiation.
Differentiation and Proliferation Characteristics of hUC-MSCs
hUC-MSCs possess properties that promote tissue repair and regulate immune responses, making them a promising therapeutic agent for diseases such as cancer. They can also serve as feeder layers for embryonic stem cells or other pluripotent stem cells, collaborating with other stem cells to enhance their effects. MSCs exhibit the ability to adhere, clone, and express unique cell surface phenotypes, as well as a high degree of scalability. They can differentiate into various cell lineages, functioning as primitive stem cells that can be directed to form adult cells with specific functions, such as neural tissue, islet-like cells, epithelial cells, and vascular endothelial cells. These differentiated cells participate in repairing damaged tissues, restoring normal body functions, and achieving therapeutic effects, thereby making hUC-MSCs a highly potential research subject in the field of regenerative medicine.The differentiation capacity of hUC-MSCs is remarkable. In addition to their ability to differentiate into adipocytes, osteoblasts, and chondrocytes, studies have also shown their potential to differentiate into neural cells, epithelial cells, cardiomyocytes, and other cell types.
The Immunomodulatory Function of hUC-MSCs
Numerous studies have demonstrated the potent immunomodulatory capabilities of MSCs. MSCs secrete a variety of biomolecules and mediators that inhibit the secretion of proinflammatory cytokines and enhance the survival of damaged cells. They can regulate the cytokine secretion of dendritic cells, macrophages, and monocytes, with the secreted cytokines inducing a shift towards an anti-inflammatory phenotype in macrophages. Due to the absence of human leukocyte DR antigens and costimulatory molecules on their cell surface, MSCs exhibit low immunogenicity. Consequently, MSCs can influence cellular immune functions, exerting an immunosuppressive effect that confers numerous benefits in disease treatment.
Research has found that MSCs can migrate towards injured skin tissue and sites of inflammation, promoting skin tissue regeneration, wound healing, reducing scar formation, alleviating skin inflammation, improving fibrosis, treating systemic sclerosis, and mitigating skin damage. The stem cell properties of MSCs have garnered increasing attention in the study of numerous disease treatments. However, given the inherent variability in diseases and patient conditions, multiple factors, including transplantation methods, infusion doses, and treatment durations, must still be considered in the therapeutic process for many diseases.
hUC-MSCs in the Treatment of Organ Injuries
1. Treatment of Organ Injuries
Organ injuries typically arise from damage or disease to the original tissue cells, disrupting tissue homeostasis and triggering a cascade of inflammation, necrosis, and related complications. While normal tissue cells can undergo some degree of self-repair, severe injuries often require medical intervention for auxiliary treatment. MSCs, with their efficient differentiation and proliferation abilities and low immunogenicity post-transplantation, have emerged as a highly promising therapeutic option. MSC-based therapies have been shown to induce complex interactions among various cell types, extracellular matrix components, and signaling molecules following injury, playing a pivotal role in promoting wound healing, maintaining tissue homeostasis, and reducing scar formation.
Studies have investigated the effect of hUC-MSCs in downregulating HIF-1α and VEGF expression in rat liver injury models. After 8 weeks of treatment, significant improvements were observed in liver histopathology, with reduced hepatocyte steatosis, fewer lipid droplet vacuoles, and alleviated inflammatory responses. The therapeutic effects of MSCs are primarily mediated through paracrine mechanisms, supporting wound healing. Although systemically administered MSCs accumulate at the injury site early on, few MSCs permanently engraft within the tissue, underscoring the safety of MSC-based cell therapies.
2.Treatment of Neurological Diseases
hUC-MSCs possess the capability to be induced into neural stem cells (NSCs) in terms of morphological characteristics, phenotype, and function, thereby achieving therapeutic effects on neurological diseases. As a novel treatment modality, they are being investigated for various peripheral or central nervous system injuries. Research has revealed that the MG53 protein exerts protective effects on neuronal cells in the brains of Alzheimer's disease mouse models. It regulates oxidative stress in the brain through the Nrf2 pathway, enhancing overall cognitive abilities and alleviating depressive symptoms in mice. Additionally, MG53 exhibits a synergistic effect when combined with hUC-MSC transplantation.
hUC-MSCs represent a valuable therapeutic approach for neurodegenerative ocular diseases. Based on the potential of MSCs to differentiate into NSCs and neurons, local MSC transplantation is being explored as a treatment for glaucoma, optic neuritis, ischemic optic neuropathy, and diabetic retinopathy, among other neurodegenerative eye conditions. Furthermore, the development of drugs targeting specific signaling pathways in conjunction with stem cell therapy is underway to enhance therapeutic outcomes.
3.Research on the Treatment of Endocrine Diseases
In the context of diabetes treatment, hUC-MSCs can release various immunosuppressive factors such as transforming growth factor-β1 (TGF-β1) and nitric oxide (NO), inhibiting the autoimmune destruction process resulting from T-cell proliferation and pancreatic islet B-cell apoptosis. Additionally, hUC-MSCs secrete multiple cytokines that interact with B-cells, dendritic cells, and other immune cells, exerting immunomodulatory effects and indirectly preventing the onset of diabetes. Studies on type 1 diabetic mice treated with human umbilical cord mesenchymal stem cells (hUC-MSCs) combined with immunomodulatory interventions have shown that both stem cell therapy and immune intervention improve islet function. While both treatments are effective, their combined application yields even better results. Animal experiments and small-scale clinical studies have demonstrated that MSC transplantation can improve pancreatic islet β-cell function in type 2 diabetic animals, reduce insulin requirements in type 2 diabetic patients, and enhance HbA1c levels and C-peptide secretion, offering a novel therapeutic strategy for glycemic control in diabetes.
Safety Research of hUC-MSC Clinical Treatment
During the transplantation process, hUC-MSCs may potentially elicit adverse reactions such as transfusion reactions, infections, hemolytic reactions, and viral infections. Recent studies have also suggested that stem cell transplantation may lead to complications like microinfarcts, thrombotic microangiopathy, and hepatic veno-occlusive disease. Therefore, prior to the widespread clinical application of hUC-MSCs, it is imperative to conduct a thorough assessment of the patient's overall condition, recognize potential safety concerns, and strive to prevent or minimize the occurrence of adverse effects.
In early MSC preclinical and clinical trials, the safety of MSC transplantation has been well-documented in both animal models and human studies. Furthermore, hUC-MSCs have been intravenously administered to non-human primates for safety testing, with no reports of stem cell transplantation-related complications. All injection sites and organs remained normal, and no tumors were detected. Additionally, the injection and transplantation of hUC-MSCs into allogenic rat models yielded favorable engraftment and functional outcomes, with no instances of immune rejection or tumor development. Nevertheless, extensive and long-term clinical studies are still necessary to ensure the safety of hUC-MSCs in relevant applications. Moreover, several aspects of hUC-MSC cell therapy require further investigation during the cell infusion process, including cell source, dosage, route of administration, and particularly, the most optimal disease treatment stage.
hUC-MSCs possess numerous attractive advantages, including a non-invasive collection process, efficient in vitro isolation and purification, low infection risk, non-tumorigenicity, remarkable multipotency, and low immunogenicity with no allogeneic rejection. When xenogeneic MSCs enter the body, they can avoid the risk of tumorigenesis caused by cell mutation due to inadequate immune surveillance. Currently, hUC-MSCs have demonstrated promising therapeutic effects in the treatment of various diseases. They have shown considerable efficacy in the management of diseases where traditional treatments have significant limitations, such as organ damage, neurological disorders, and endocrine system diseases. Both in animal models and in clinical applications on humans, hUC-MSCs have brought new hope for the treatment of an increasing number of diseases.
References
[1] Zhang Xuejuan, Sun Xuyan, Yang Weijuan, Zhang Xiutao, Gao Zongsheng, Sun Hongtao. "Research Progress on the Functionality and Clinical Application of Human Umbilical Cord Mesenchymal Stem Cells." Chinese Journal of Contemporary Medicine, 2021, 28(27): 39-43.
[2] Feng Lei, Cao Ning, Liang Suli, Feng Chun, Guo Lei. "Research Progress on the Clinical Application of Umbilical Cord Mesenchymal Stem Cells and Umbilical Cord Blood Hematopoietic Stem Cells." Chinese Journal of Maternal and Child Health (Electronic Version), 2014, 10(03): 387-392.
About the Author
Xiaonisha, a food technology professional holding a Master's degree in Food Science, is currently employed at a prominent domestic pharmaceutical research and development company. Her primary focus lies in the development and research of nutritional foods, where she contributes her expertise and passion to create innovative products.
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