In this article, we will explore various therapeutic approaches utilizing mesenchymal stem cells (MSCs).
MSC-Based Therapeutic Strategies
Although the heterogeneous characteristics of MSCs and their exact mechanisms of action at the cellular and molecular levels have not yet been fully elucidated, MSC-based therapies—whose safety has been consistently validated in clinical trials—are rapidly advancing in two major directions: (1) tissue regeneration through differentiation potential, and (2) immunomodulation and anti-inflammatory effects. While complete functional tissue regeneration has not yet been achieved in various clinical trials aimed at regenerating joint cartilage or liver tissue, progress is gradually being made. Most clinical studies are still in the intermediate stages, and as of now, there appear to be no internationally approved MSC therapies specifically for regenerative purposes.
For patients with bone loss, the most effective method of bone reconstruction is autografting, or transplanting bone from another part of the patient’s own body. Living bone tissue contains osteocytes, hematopoietic stem cells, MSCs, extracellular matrix, and vascular networks—all of which make it the most reliable and regeneration-optimized approach. However, the amount of bone that can be harvested is very limited, and there is a risk of complications at the donor site. Therefore, a more commonly used clinical approach is to extract a small amount of autologous bone and combine it with scaffolds or hydrogels to form a structural framework.
Cartilage regeneration therapies appear to be more developed than bone regeneration methods. For example, Matrix-induced Autologous Chondrocyte Implantation (MACI) was the first FDA-approved treatment. In this personalized therapy, a patient’s own chondrocytes are collected, cultured, and seeded onto a collagen matrix, which is then implanted back into the damaged cartilage area of the knee [1]. Recently, MSCs have been added to this process—not primarily for their direct differentiation into bone or cartilage, but for their paracrine role in secreting growth factors and cytokines that stimulate surrounding osteoblasts and angiogenesis.
Furthermore, therapies that induce regeneration by constructing scaffolds solely with MSCs, without patient-derived bone tissue, are also being studied. Scaffolds, which are biodegradable, three-dimensional structures, serve as physical and chemical environments that allow cells to adhere, grow, and gradually form tissue—essentially acting like a structural “house.” Scaffolds come in various forms: thin membranes (sheets) such as collagen films, rigid porous blocks made from ceramics or synthetic polymers, and hydrogels that retain large amounts of water. The choice of scaffold type depends on the target tissue—rigid scaffolds for bones, elastic and lubricated scaffolds for cartilage, and soft ones for skin. Scaffolds serve as temporary platforms that induce tissue regeneration and provide structural support while the tissue heals.
If technologies are developed that can reliably direct MSCs to differentiate in desired lineages, true stem cell-based bone regeneration could become possible—potentially the most ideal treatment approach. Such a therapy would reduce both treatment costs and the pain associated with tissue harvesting and transplantation. Currently, however, most research focuses on the paracrine functions of MSCs—stimulating the growth of surrounding cells—and on combining these effects with other fields such as biomaterials, genetic engineering, and extracellular vesicle (EV)-based therapies to achieve synergistic outcomes. Let us now take a closer look at the types of MSC-based therapies under development and their future directions.
Pre-conditioning
As discussed earlier, MSCs can exhibit both inflammatory and anti-inflammatory phenotypes. Factors that induce polarization or switching toward the anti-inflammatory phenotype include hypoxic environments, specific cytokines (such as IFN-γ, TNF-α, and IL-1), and activation of certain pattern recognition receptors (like TLR-3). To enhance the immunosuppressive properties of MSCs, preconditioning (or pre-licensing)—the process of exposing MSCs to these factors before therapeutic use—has become a widely adopted strategy. Other related approaches include cell-free therapies that utilize extracellular vesicles (exosomes) secreted by MSCs, genetic engineering to overexpress chemotactic factors to improve MSC homing ability to injury sites, and encapsulation using biomaterials such as hydrogels.
Extracellular Vesicle (EV)-Based Therapies Derived from MSCs
The field of Drug Delivery Systems (DDS) aims to maximize therapeutic efficacy while minimizing side effects by delivering drugs selectively to diseased tissues. Among the most promising recent technologies in this field are nanoparticle-based delivery systems, particularly those using extracellular vesicles (EVs)—naturally secreted particles from cells—which are emerging as next-generation carriers that could replace synthetic nanoparticles.
EVs exhibit high biocompatibility, elicit minimal immune rejection (unlike synthetic nanoparticles), and are capable of crossing biological barriers such as the blood-brain barrier (BBB)—giving them enormous potential for the treatment of various intractable diseases. Because they are naturally derived, EVs are also relatively stable, and—unlike MSCs—they are easier to store and transport, remaining stable during long-term cryopreservation at −80°C without loss of activity, even after repeated freeze-thaw cycles [2].
Notably, MSC-derived EVs are rich in paracrine factors and can replicate most of the therapeutic effects of MSCs, including immunomodulation, anti-inflammatory action, and tissue regeneration. When MSCs themselves are used as therapeutic agents, there is a potential risk that their homing ability could lead them into tumor microenvironments, promoting cancer cell growth. Additionally, long-term culture may cause cellular aging, chromosomal instability, or mutations. EVs, however, contain no nuclei and therefore cannot replicate, eliminating the risk of tumor formation. Thus, EV-based therapeutics are emerging as a safer alternative that preserves the benefits of MSC therapy while avoiding its cancer-related safety concerns.
A recent study demonstrated that EVs derived from adipose tissue MSCs loaded with the anticancer drug paclitaxel significantly inhibited the proliferation of target tumor cells. Although the effect was not stronger than direct paclitaxel administration, the key advantage lies in EVs’ modifiable surfaces, which allow for more efficient uptake by target cells or tissues, thereby reducing toxicity and side effects. Additionally, EV lipid membranes remain intact against enzymatic degradation and are naturally absorbed by cells, enhancing delivery efficiency [3].
However, the therapeutic effects of MSC-derived EVs can vary greatly depending on the tissue origin of MSCs and culture conditions, making it difficult to achieve uniform and consistent outcomes. This variability is closely related to the heterogeneity inherent in the parent MSCs themselves.
Heterogeneity of MSCs
The reason MSCs are considered heterogeneous lies in their diverse tissue origins—including bone marrow, adipose tissue, umbilical cord blood, dental pulp, and synovium—each of which produces MSCs with distinct gene expression profiles, immunomodulatory capacities, and growth factor secretion patterns. Consequently, even MSCs classified under the same name can differ significantly in their biological characteristics. As a result, the composition of miRNAs, proteins, and lipids within the EVs secreted by these cells also varies depending on their source.
Furthermore, even MSCs derived from the same tissue are not a homogeneous population; some subgroups differentiate more readily into osteocytes, others into adipocytes, and still others into chondrocytes. Therefore, rather than being a uniform population, MSCs are a mixture of heterogeneous progenitor cells possessing multiple developmental potentials. Adding to this complexity, environmental conditions and signaling cues can polarize MSCs toward either pro-inflammatory or anti-inflammatory phenotypes, indicating that they are an extremely plastic population. This inherent heterogeneity is directly reflected in the characteristics of the EVs they secrete.
Depending on the source, MSCs can be classified into those derived from adipose tissue, umbilical cord, bone marrow, or placenta, and each group shows different strengths in functional aspects. Adipose-derived MSCs have a strong effect in supporting the hematopoietic stem cell niche and are advantageous in promoting angiogenesis. Umbilical cord-derived MSCs have stable proliferative ability, maintain their stem cell properties even after long-term culture, and show stronger differentiation potential into osteocytes, chondrocytes, and adipocytes compared to bone marrow-derived MSCs. In addition, they have been shown to exhibit the most powerful immunosuppressive effects, making them particularly promising for the treatment of autoimmune diseases and immune disorders such as graft-versus-host disease (GvHD). Bone marrow-derived MSCs have been the most extensively studied to date, but their proliferative stability is lower than that of umbilical cord-derived MSCs, and their immunosuppressive ability is weaker than that of adipose- or umbilical cord-derived MSCs, so they are mainly used in studies focused on bone or cartilage regeneration. Placenta-derived MSCs show weaker immunosuppressive effects than umbilical cord-derived MSCs, but they have the advantages of being easy to obtain and posing fewer ethical issues, making them a good alternative resource for regenerative medicine research. These differences in the composition of subtypes and specific strengths depending on the source lead to limitations in the predictability and consistency of EV-based therapies. Therefore, current EV-based therapeutics face the task of reducing such heterogeneity and standardizing and defining which EVs can produce the optimal therapeutic effects under specific conditions.
Hydrogel Encapsulation
MSCs encapsulated in hydrophilic polymer hydrogels with high water content exhibit enhanced engraftment and improved immunomodulatory functions in vivo, leading to better therapeutic outcomes. Cell-based therapy utilizes living cells that dynamically respond to biological signals to attack tumors, regenerate tissues, restore lost biological functions, or enhance the body’s ability to combat disease. Compared to conventional small-molecule drugs or biologics, cell-based therapies offer unique clinical and therapeutic advantages, as living cells can perform complex biological functions that traditional drugs cannot. This cutting-edge biotechnology platform can respond simultaneously to systemic/local, chemical, physical, and biological signals, easily traverse biological barriers, and precisely target specific cell types or tissues. The major cell types used are stem cells and tissue-specific cells (e.g., skin or cartilage cells), with hematopoietic stem cells (HSCs) and MSCs being the most widely approved for therapeutic use [4].
When MSCs are cultured and transplanted—whether intravenously or locally—less than 5% of the injected cells typically reach the target tissue. Therefore, strategies must be devised to improve MSC survival and engraftment efficiency in vivo. One such approach involves modifying the cellular microenvironment using biomaterials such as hydrogels. Hydrogels can be derived from natural sources such as collagen or hyaluronic acid, from synthetic polymers, or from hybrid semi-synthetic materials. Owing to their diverse physicochemical properties, hydrogels are extensively applied in biomedical research.
When MSCs are encapsulated within a hydrogel, the material physically supports the cells while mimicking the extracellular matrix (ECM) by providing adhesion sites and a microenvironment conducive to oxygen and nutrient diffusion and waste removal. This setup increases MSC viability and significantly improves in vivo retention. By tuning hydrogel properties such as stiffness, elasticity, and porosity, researchers can modulate the secretion profiles of encapsulated MSCs. If living MSCs are embedded within a hydrogel, the product is classified as a cell-based therapy; if the hydrogel instead contains MSC-derived bioactive factors such as EVs, growth factors, or miRNAs, it constitutes a cell-free therapy.
MSCs as Carriers for Oncolytic Viruses (OVs)
Oncolytic viruses (OVs) are genetically engineered viruses designed to selectively infect and destroy cancer cells. Their genomes are modified so that replication occurs exclusively within cancer cells, sparing normal cells, and additional antitumor genes are inserted to enhance immune activation. When injected into the body, these viruses infect and lyse tumor cells, releasing viral particles that subsequently infect neighboring cancer cells in a cascade of oncolysis. This process also stimulates immune cells, including T cells, to mount a strong antitumor immune response capable of eliminating cancer cells.
Talimogene Laherparepvec (T-VEC) was the first FDA-approved oncolytic virus, used for treating inoperable skin cancers such as melanoma [5]. This therapeutic virus carries the GM-CSF (granulocyte-macrophage colony-stimulating factor) gene, which recruits antigen-presenting cells such as dendritic cells and macrophages to the tumor site. These, in turn, help activate cytotoxic T cells that can directly kill tumor cells and contribute to adaptive immunity. MSCs are being explored as delivery vehicles to safely transport these oncolytic viruses to target tumor cells [6]. Unlike most stationary somatic cells, MSCs can migrate through the bloodstream and home to sites of tissue injury or inflammation. Leveraging this homing ability, MSCs can act as “Trojan horses,” carrying the oncolytic viruses within them. This strategy helps protect the viruses from immune clearance, allowing them to reach their target destination safely. Among various MSC sources, adipose-derived MSCs—which are easy to harvest and abundant—are being extensively investigated for use in oncolytic virus-based cancer therapies.
Outlook and Challenges
MSC-based therapies have recently gained significant attention, yet long-term follow-up studies are still needed to verify the consistency and durability of therapeutic effects. Because these treatments involve living cells, outcomes may vary depending on culture conditions, patient status, and delivery routes. Moreover, more safety data are needed to assess potential side effects from repeated or long-term administration. Despite these challenges, the potential of MSC-based therapies as next-generation immunotherapeutics for an expanding range of immune-related diseases remains high, driving ongoing research and clinical interest.
Approved MSC-Based Therapeutics
In Japan, TEMCELL® has been approved for the treatment of acute graft-versus-host disease (GvHD). In Europe, Alofisel® was approved for treating Crohn’s disease-related fistulas, although it was withdrawn from the market at the end of 2024. In the United States, Ryoncil, a bone marrow-derived MSC therapy for steroid-refractory acute GvHD in pediatric patients, received FDA approval in late 2024—becoming the first and only FDA-approved MSC therapy in the U.S. In Korea, several MSC-based drugs are registered with the Ministry of Food and Drug Safety (MFDS).
[References]
[1] MACI - a new era?
doi: 10.1186/1758-2555-3-10
[2] Mesenchymal stem cell-derived extracellular vesicles for immunomodulation and regeneration: a next generation therapeutic tool?
https://doi.org/10.1038/s41419-022-05034-x
[3] Extracellular vesicles isolated from adipose tissue-derived mesenchymal stromal cells as carriers for Paclitaxel delivery
https://doi.org/10.1186/s13287-025-04435-x
[4] Cell therapies in the clinic
doi: 10.1002/btm2.10214
[5] Talimogene Laherparepvec (T-VEC): An Intralesional Cancer Immunotherapy for Advanced Melanoma
doi: 10.3390/cancers13061383
[6] Mesenchymal Stem Cells for the Delivery of Oncolytic Viruses in Gliomas
doi: 10.1016/j.jcyt.2017.02.002
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