Mesenchymal Stem Cells (MSCs)

Stem cells are a unique type of cell found in nearly every tissue type throughout the lifespan of multicellular organisms. Their primary functions include facilitating tissue development, maintaining homeostasis, and repairing tissue damage. Stem cells are characterized by their capacity for self-renewal, multipotency or pluripotency, and clonality. They are classified into two main categories: embryonic stem cells and adult stem cells.

Mesenchymal Stem Cells (MSCs) are a subset of adult stem cells naturally present in the body. These undifferentiated cells are located in various tissues and play a critical role in replenishing dying cells and regenerating damaged tissues. Beyond bone marrow, MSCs have been identified in a variety of tissues, including adipose tissue, peripheral blood, spleen, brain, synovial fluid, dermis, muscle, dental pulp, umbilical cord, placenta, skin, liver, pancreas, and intestines, where they can differentiate into several mesenchymal lineages [1-3].

However, there are significant differences in the proliferation and differentiation abilities, as well as in the harvesting procedures among these MSCs. In 2007, the International Society for Cellular Therapy (ISCT) established criteria for defining MSCs, which include adherence to plastic in standard culture conditions, expression of specific surface markers (≥95% CD105, CD73, CD90; ≤2% CD45, CD34, CD14, CD11b, CD79a, CD19, HLA-DR), and the ability to differentiate into at least three lineages: osteoblasts, adipocytes, and chondrocytes .

Despite these criteria, the isolation of stem cells remains a significant challenge due to the absence of universally accepted markers. Controversies persist regarding the reproducibility of results from published methods, particularly concerning differentiation protocols [5-9]. Additionally, different isolation methods can significantly impact the differentiation potential of adult stem cells [10-11]. There is a limited number of studies comparing the differentiation capacity of stem cells obtained from various sources using the same differentiation protocols [12-17]. The inconsistency between established protocols across different laboratories complicates the interpretation of previously reported data.

Since the identification of their multi-lineage potential in 1999, MSCs have generated considerable interest in the biomedical field. They can differentiate into various cell types and produce important growth factors and cytokines [19-20]. Furthermore, MSCs can modify immune cell responses, making them relevant in treating immune-related disorders, particularly autoimmune diseases [21-22].

Although MSCs are widely distributed throughout the body, bone marrow remains the principal source for most MSC-based preclinical and clinical studies, where they are primarily characterized after isolation. However, MSCs are relatively rare in bone marrow aspirates, with frequencies of approximately 1 in 1,000,000 nucleated cells in adult bone marrow and 1 in 10,000 nucleated cells in umbilical cord blood. The number of MSCs tends to decrease with age. More primitive MSCs have since been discovered, including those immunomagnetically separated and referred to as mesodermal progenitor cells (MPCs) or multipotent adult progenitor cells (MAPCs).

Expansion of Mesenchymal Stem Cells (MSCs) is essential for clinical applications. Although MSCs are rare in the human body, they can be expanded in vitro to produce hundreds of millions of cells by adhering to plastic and undergoing successive passaging. In confluent cultures, MSCs typically proliferate into spindle-shaped cells. Despite appearing homogeneous under light microscopy, single-cell-derived colonies can exhibit molecular heterogeneity and variability in their differentiation capacity.

Even when MSCs are expanded significantly, individual cells in a culture show highly variable expansion potential. The yield of expanded MSCs can be influenced by the donor’s age and condition, as well as the harvesting techniques employed. Variations in isolation methods, culture conditions, media additives, and sub-culturing techniques can greatly affect cell yield and potentially alter the phenotype of the expanded cell product. While moderate subcultivation does not change the karyotype or telomerase activity of MSCs, excessive passaging can lead to signs of senescence and apoptosis.

The Potential Clinical Use of Mesenchymal Stem Cells (MSCs)

Recent advancements in understanding mesenchymal stem cell (MSC) biology have opened the door to their potential clinical applications. This new era in disease treatment emerged with the discovery of stem cells from diverse tissues and organs. A growing body of evidence suggests that one of the mechanisms through which MSCs provide tissue protection and repair involves paracrine factors, including cytokines and growth factors secreted by transplanted MSCs into surrounding tissues (28). Furthermore, MSCs themselves release a variety of pro-inflammatory and anti-inflammatory cytokines, which play a significant role in immune modulation (29).

MSCs are also advantageous for allogeneic transplantation because they are immune-privileged, meaning they express low levels of major histocompatibility complex I (MHC I) and lack MHC II expression, reducing the risk of allogeneic transplant rejection (30).

Despite their widespread potential, different MSCs, depending on their tissue origin, may exhibit varied differentiation capacities, even when cultured in the same environment. The therapeutic potential of MSCs has attracted increasing interest across various biomedical disciplines. However, the variability in cell isolation and characterization methods makes comparing study outcomes difficult, thereby hindering progress in the field. Establishing a recognized standard for evaluating MSC characteristics is crucial (31).

Cardiovascular Therapeutic Potential

The cardiovascular therapeutic potential of bone marrow-derived MSCs is primarily driven by paracrine effects. Traditionally, MSCs are prepared using plastic adherence-isolation techniques. However, newer methods such as prospective immunoselection have been developed to improve cell isolation by enriching mesenchymal precursor cells (MPCs) with higher purity (32).

A study comparing MSCs isolated by plastic adherence to MPCs selected using stromal precursor antigen-1 (STRO-1) showed that STRO-1-MPCs exhibited greater clonogenicity, proliferative capacity, and multilineage differentiation potential compared to plastic adherence-isolated MSCs. STRO-1-MPCs also had enhanced paracrine activity, particularly in promoting cardiac and endothelial cell proliferation, migration, and tube formation (33). These findings indicate that STRO-1 enrichment is associated with greater cardiovascular-relevant cytokine expression and improved trophic activity, making it an essential consideration in optimizing MSC-based cardiovascular therapies (34).

The use of MSCs in treating ischemic heart disease and heart failure has gained traction in the past decade. While most studies have employed MSCs prepared by plastic adherence-isolation, this method is limited by the low frequency of clonogenic cells and contamination with more mature stromal and non-mesenchymal cells (35). The isolation of pure MPC populations, such as those expressing STRO-1, offers a promising alternative and highlights the importance of precision in cell therapy for improving cardiovascular outcomes (36).

Novel Wound Healing Promotion Therapy

Chronic wounds remain challenging to treat, with limited progress in improving healing outcomes over recent decades (37). Innovative treatments are needed to promote wound healing and tissue regeneration. MSCs have shown potential in this area due to their ability to promote re-epithelialization and modulate the extracellular matrix, particularly through interactions with hyaluronic acid (HA) (38).

Stem cells from human exfoliated deciduous teeth (SHED) have also demonstrated significant potential for wound healing, offering advantages over MSCs, particularly in elderly patients, where MSC proliferation and differentiation capacity decline (39). SHED cells have been found to significantly enhance wound healing compared to human fibroblasts, offering an innovative therapeutic approach (40).

 

Implications in Treating Liver Diseases

The immunoregulatory functions of MSCs hold promise for treating liver diseases such as fulminant hepatic failure and end-stage liver diseases. In both preclinical and clinical trials, MSCs have been shown to reduce inflammatory injury, hepatocyte apoptosis, and liver fibrosis by modulating the immune response (41). Although MSC therapy for liver disease shows promise, further research is needed to optimize therapeutic protocols, such as determining optimal doses, transplantation intervals, and administration routes (42).

Anti-Inflammatory and Anti-Tumor Effects

MSCs have demonstrated anti-tumor activity against pancreatic cancer cells (PANC-1) and have been explored as delivery vehicles for interferon-beta (IFN-β) in cancer therapies. However, these effects may be diminished when combined with anti-inflammatory agents (43). In addition, MSC therapy’s primary mechanisms—such as modulating inflammation, cell death, and fibrosis—are linked to the secretion of trophic factors like cytokines and growth factors, which are often sufficient to achieve therapeutic effects (44).

Other Diseases

MSC transplantation has shown potential as a treatment for numerous diseases, including blood disorders, diabetes (type 1 and type 2), osteoarthritis, lung disease, spinal cord injuries, liver injury, stroke, myocardial infarction, and autoimmune diseases like systemic lupus erythematosus (SLE) (45). Hundreds of clinical trials involving MSCs are registered with the U.S. National Institutes of Health (NIH), highlighting the need for ongoing research to identify the most promising stem cell sources and optimize their therapeutic potential (46).

The success of stem cell-based therapies depends on factors such as cell availability, differentiation potential, and the immune response following transplantation. Identifying suitable MSC types for specific therapeutic applications remains a critical step toward realizing the full potential of regenerative medicine (47).

 

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