Controversies regarding transplantation of mesenchymal stem cells

Table 1 The most common immunological mechanisms employed by mesenchymal stem cells

Properties	Mechanisms	Ref.
Suppression of T-cell proliferation	MSCs are adept at inhibiting the proliferation and activation of T lymphocytes, a vital component of the adaptive immune response. This effect is mediated by releasing soluble factors such as IDO and PGE2, which create an immunosuppressive microenvironment	[15,16]
Induction of Tregs	MSCs promote the generation and expansion of regulatory T cells, or Tregs, which play a crucial role in immune tolerance and suppressing excessive immune reactions. This induction of Tregs is partly attributed to interactions between PD-L1 on MSCs and PD-1 on T cells	[17-19]
Modulation of DCs	MSCs influence the maturation and function of DCs, pivotal antigen-presenting cells in the immune system. They inhibit the expression of co-stimulatory molecules on DCs and reduce their ability to activate T cells, thereby tempering immune responses	[20]
Reduction of inflammatory cytokines	MSCs secrete anti-inflammatory cytokines like IL-10, TGF-β, and HGF, while simultaneously dampening the production of pro-inflammatory cytokines, including IFN-γ	[21,22]
Promotion of macrophage polarization	MSCs can skew macrophages towards an anti-inflammatory, tissue-healing M2 phenotype, fostering a regenerative environment and mitigating tissue damage	[23]
Immune cell anergy	MSCs can induce a state of anergy in T cells, rendering them functionally inactive and refractory to activation signals. This effect is conducive to immune tolerance and reduced autoimmune responses	[24]
Exosome-mediated communication	MSCs release immunomodulatory exosomes that carry bioactive molecules, including microRNAs and proteins, capable of regulating immune cell behavior and suppressing inflammation	[25]

Tregs: Regulatory T cells; IDO: Indoleamine 2,3-dioxygenase; PGE2: Prostaglandin E2; PD-L1: Programmed death-ligand 1; PD-1: Programmed cell death protein 1; DCs: Dendritic cells; MSCs: Mesenchymal stem cells; IL-10: Interleukin-10; TGF-β: Transforming growth factor-beta; HGF: Hepatocyte growth factor; IFN-γ: Interferon-gamma.

Table 2 The clinical potential of mesenchymal stem cells

Application	Effects	Ref.
Musculoskeletal disorders	MSCs have shown great promise in treating musculoskeletal conditions, including osteoarthritis, rheumatoid arthritis, and bone fractures. Their ability to differentiate into bone and cartilage cells and their anti-inflammatory properties make them valuable for tissue repair and regeneration	[28]
Cardiovascular diseases	MSCs exhibit cardio-protective effects and can enhance cardiac repair following myocardial infarction. Clinical trials have explored their potential for improving heart function, reducing scar formation, and stimulating angiogenesis	[29]
Neurological disorders	MSCs hold potential for treating neurodegenerative conditions such as Parkinson's disease, Alzheimer's disease, and spinal cord injuries. They promote neuroprotection, neural differentiation, and the secretion of neurotrophic factors, fostering neural tissue repair	[30]
Autoimmune disorders	In autoimmune diseases like multiple sclerosis and systemic lupus erythematosus, MSCs' immunomodulatory properties help suppress aberrant immune responses and reduce disease severity. They promote tolerance and reduce inflammation	[31,32]
GVHD	MSCs have demonstrated effectiveness in managing GVHD, a potentially fatal complication of hematopoietic stem cell transplantation. They modulate immune reactions, aiding in GVHD prevention and treatment	[33]
IBD	MSCs are under investigation for their role in managing Crohn's disease and ulcerative colitis. They promote mucosal healing, reduce inflammation, and regulate the immune system within the gut	[34]
Diabetes	MSCs hold the potential for treating type 1 diabetes by promoting pancreatic beta-cell regeneration and modulating the autoimmune response that leads to beta-cell destruction	[35]
Wound healing and dermatological conditions	MSCs facilitate wound healing by enhancing tissue regeneration and reducing scar formation. They are explored for treating skin conditions like chronic ulcers and epidermolysis bullosa	[36]
Lung disorders	In conditions like COPD and idiopathic pulmonary fibrosis, MSCs can mitigate inflammation, promote lung tissue repair, and enhance pulmonary function	[37]

COPD: Chronic obstructive pulmonary disease; GVHD: Graft-versus-host disease; IBD: Inflammatory bowel disease; MSCs: Mesenchymal stem cells.

Table 3 Future directions in mesenchymal stem cell treatments

Aspect		MSC treatment
Personalized medicine	Patient-specific MSCs	One of the critical strategies in personalized medicine involves using patient-derived MSCs. These autologous MSCs are obtained from the patient's own tissues, such as bone marrow or adipose tissue. Using a patient's cells minimizes the risk of immune rejection, and treatment can be tailored to the individual's needs
	Genomic and molecular profiling	Advances in genomics and molecular profiling techniques enable the identification of specific markers or genetic characteristics that influence a patient's response to MSC therapy. This information can guide treatment decisions, allowing for the selection of the most appropriate MSC source and optimization of the therapeutic regimen
	Disease-specific approaches	Tailoring MSC therapies to the unique features of a particular disease is another aspect of personalized medicine. For example, MSCs can be engineered in cancer therapy to deliver anti-tumor agents or enhance immune responses, depending on the patient's cancer type and stage
	Dosage and timing optimization	Personalized medicine also extends to optimizing the dosage and timing of MSC treatments. Factors such as the severity of the condition, the patient's age, and comorbidities can all influence the treatment protocol, ensuring the best possible outcomes
Advanced delivery methods	Microencapsulation and biomaterials	Microencapsulation involves encapsulating MSCs within biocompatible materials or hydrogels. This protective environment shields MSCs from immune responses while providing a sustained release of therapeutic factors. This approach is encouraging for conditions like diabetes, where encapsulated MSCs can help regulate blood sugar levels
	Intravenous infusion techniques	Intravenous delivery of MSCs is a common method, but refinements in infusion techniques are being explored to maximize cell retention and tissue homing. Pre-conditioning or priming MSCs before infusion can enhance their migratory properties and tissue-specific targeting
	Nanoparticle-based carriers	Nanoparticles can serve as carriers for MSCs, protecting them during transit and improving their ability to reach target sites. These carriers can be loaded with therapeutic or imaging agents for tracking and treatment monitoring
	Direct injection and endoscopic delivery	For localized conditions, such as osteoarthritis or IBD, direct injection of MSCs into the affected area or endoscopic delivery methods are being refined to target tissues and minimize invasiveness precisely
	Exosome-mediated delivery	MSC-derived exosomes, tiny vesicles containing bioactive molecules, offer a cell-free approach to therapy. Exosomes can be isolated and administered to mediate therapeutic effects, making them a promising alternative to whole-cell therapy
Combining therapy	Immunomodulatory Combinations	Combining MSC therapy with immunomodulatory agents or immune checkpoint inhibitors can potentiate the immunosuppressive effects of MSCs, particularly in the context of autoimmune diseases or organ transplantation
	Gene editing and engineering	Genetic modification of MSCs allows for the precise manipulation of their properties. Engineered MSCs can be equipped with therapeutic genes or targeted for specific functions, such as enhancing tissue regeneration or tumor suppression
	Drug delivery systems	MSCs can serve as drug delivery vehicles, transporting therapeutic compounds directly to diseased tissues. This approach is particularly relevant in cancer therapy, where MSCs can deliver anti-cancer drugs to tumor sites
	Stem cell combinations	Combining different types of stem cells, such as iPSCs or neural stem cells, with MSCs can offer multi-pronged approaches to conditions like spinal cord injuries or neurodegenerative diseases
	Adjunct therapies	MSC transplantation can complement traditional treatments, such as surgery or radiation therapy. For example, MSCs can be used alongside surgical procedures in bone repair to accelerate healing and improve outcomes

MSC: Mesenchymal stem cell; IBD: Inflammatory bowel disease; iPSCs: Induced pluripotent stem cells.