A Closer Look at Mesenchymal Stem Cells (MSCs), Their Potential and Function as Game-Changers of Modern Medicine

Abstract

Mesenchymal stem cells (MSCs) have garnered significant attention in modern medicine as a potentially effective therapeutic intervention, owing to their distinctive characteristics, including the ability to self-renew, exhibit multipotency, elicit immunomodulatory effects, and promote tissue repair. MSCs are being studied extensively for their potential use in a wide range of clinical applications, including regenerative medicine, immunotherapy, and tissue engineering. In this chapter, we provide a comprehensive overview of the biology, potential, and function of MSCs, highlighting their role in modulating the immune system, promoting tissue repair, and restoring homeostasis in various disease conditions. We also discuss the challenges and limitations associated with MSC-based therapies, including issues related to their isolation, expansion, and delivery. Further research is needed to fully understand the mechanisms underlying MSCs’ therapeutic effects and to optimize their clinical application. Nevertheless, MSCs hold great promise as game-changers in modern medicine, and their potential to revolutionize the field of regenerative medicine and immunotherapy cannot be overlooked.

1. Introduction

In the 1960s, scientists led by Friedenstein initially identified a population of fibroblast-like cells in bone marrow tissue that had the unique ability to renew themselves. Ever since this landmark discovery, these cells, now known as mesenchymal stem/stromal cells, have been the target of extensive research efforts due to their intriguing characteristics [1]. MSCs represent a subset of adult stem cells distinguished by their potential to develop into different cell lineages, their self-propagating capacity, and immunoregulatory functions [2]. Their proven capacity to mature into cell types like osteocytes, chondrocytes, and adipocytes makes them highly valuable for promoting tissue repair and regeneration. Further research has shown that MSCs secrete a variety of biomolecules like growth factors, cytokines, and extracellular vehicles (EVs) involved in healing processes [3].

MSCs show great potential in the regenerative medicine field due to their unique traits and therapeutic capabilities. These cells, found in tissues like bone marrow (BM), fat, umbilical cord (UC), and dental pulp, hold significant promise for addressing many diseases and injuries [2]. Scholars have extensively investigated MSC isolation and expansion methods to benefit from their therapeutic properties. Researchers have created various isolation techniques like density centrifugation, adherence-based selection, and fluorescence-activated sorting [4]. These approaches help capture a population enriched with MSCs, which can then be grown in culture. Standardizing isolation protocols and characterization standards is crucial to make results across labs and clinical applications consistent and comparable. One remarkable MSC characteristic is immunomodulation. MSCs can alter immune responses by regulating various immune cell activities. They suppress the proliferation and functions of T cells, B cells, and natural killer (NK) cells, while promoting regulatory T cell (Treg) expansion. This immunosuppressive ability benefits autoimmune disorders, graft versus host disease (GVHD), and organ transplant treatment by curbing excessive immunity and fostering tolerance [5].

The therapeutic applications of MSCs and their derivatives like exosomes span a wide range of medical disciplines [6]. In orthopedics, MSCs have shown promise in regenerating bone and cartilage tissues, offering potential alternatives to traditional approaches such as joint replacements [7]. In cardiovascular medicine, MSCs have been investigated for their ability to improve cardiac function and promote blood vessel formation, holding the potential for treating heart failure and ischemic conditions [8]. Additionally, MSC-based therapies have shown encouraging results in neurological disorders, autoimmune diseases, and tissue injuries, demonstrating their versatility and potential to revolutionize patient care [9]. Due to these key characteristics, MSCs hold tremendous promise for regenerative medicine applications.

2. Biology and characteristics of MSCs

The International Society for Cellular Therapy (ISCT) defines human MSCs as fibroblast-like, plastic-adherent cells that express surface markers CD73, CD90 and CD105. At the same time, they lack expression of CD45, CD34, CD14 or CD11b, CD79a or CD19, and HLA-DR. According to ISCT guidelines, the ability to differentiate into osteoblasts, adipocytes, and chondroblasts when cultured in vitro is another key characteristic used to identify MSCs [10]. However, self-renewal – the process by which a single stem cell divides to produce at least one new identical stem cell – is a fundamental property of all stem cells. The ability to proliferate and generate clonal progeny through successive cell divisions while maintaining the potential to differentiate is crucial for stem cell characterization and relies on self-renewal capability [11]. Importantly, it should be noted that the expression of surface markers on MSCs may fluctuate depending on the specific tissue they are derived from, in vitro expansion protocols, and the culture conditions used. Careful phenotypic analysis is therefore required to accurately characterize MSC populations [2]. For example, the surface marker CD105, also known as endoglin and a component of the TGF-β receptor complex, has been shown to be expressed on mesenchymal stem cells derived from various tissues but with differing intensities. Research findings indicate that over 50% of liver-derived MSCs are positive for CD105, whereas less than 10% of MSCs from the amniotic membrane (AM-MSCs) and UC (UC-MSCs) express this antigen. Additionally, liver-derived MSCs were reported to have a low-level expression (5–10%) of CD45, a lineage marker that the majority of MSCs typically lack [12]. In a separate study comparing mesenchymal stem cells derived from BM (BM-MSCs) to those obtained from menstrual blood (referred to as MenSCs), distinct expression profiles were observed between the two populations. The research found that although both BM-MSCs and MenSCs lacked surface markers associated with pluripotency, namely SSEA-3, SSEA-4, and TRA-1-60, MenSCs demonstrated high levels of expression of HLA-ABC and CD49α [13]. So, proper identification of MSCs necessitates controlling for variables that can potentially impact marker expression. In terms of origin, MSCs have been identified in multiple tissues throughout the body, with sources comprising BM, adipose tissue, UC, and dental pulp, among others. Of these, MSCs derived from BM have undergone significant research and are viewed as the archetypal MSC population. However, it is important to recognize that MSCs from diverse tissues can demonstrate differences in their attributes and responses. Studies have highlighted variations in the properties of MSCs depending on their exact anatomical source. For example, a comparative study investigated the properties of MSCs isolated from BM, adipose tissue (AD-MSCs), placenta (P-MSCs), and cord blood (CB-MSCs). While all MSC types exhibited similarities in proliferation capacity, clonogenic potential (ability to form colonies), and surface marker expression, BM-MSCs and AD-MSCs demonstrated stronger osteogenic differentiation ability as determined by von Kossa staining. BM-MSCs and AD-MSCs also expressed higher, more consistent levels of the DLX-5 gene known to regulate osteogenesis [14]. Additionally, the research reported that CB-MSCs and P-MSCs lacked osteogenic potential and exhibited poor adipogenic differentiation as well [14]. Similar findings were reported in another study that compared the in vivo bone-forming capacity of MSCs derived from different tissues. Although BM-MSCs successfully generated bone tissue under the experimental conditions, AD-MSCs, UC-MSCs, and skin-derived MSCs did not exhibit the same ability to produce bone [15]. The results mirrored previous research indicating that while MSCs share a multilineage potential profile, their precise anatomical source can influence the extent of osteogenic differentiation, with BM-MSCs demonstrating superior skeletal lineage commitment ability compared to MSCs from adipose tissue, UC, and skin in this experimental setup [15].

Additionally, MSCs appear as spindle-shaped cells when observed under a microscope. They possess elongated and slender cytoplasmic extensions, enabling them to interact with their microenvironment and neighboring cells. This morphology allows MSCs to migrate to sites of injury or inflammation efficiently and participate in tissue repair processes [16].

3. Functional properties of MSCs

MSCs have an array of traits supporting their usefulness in regenerative medicine. Their immunomodulatory influences, capacity for tissue restoration and regeneration, the potential to evolve into numerous cell types, and role in regulating the microenvironment collectively underlie their therapeutic power.

3.1 Immunomodulatory effects of MSCs

The immunomodulatory function of MSCs involves complex interactions between cell-cell contact mechanisms and soluble factor secretion to regulate immune homeostasis. Both modes of action work synergistically to influence immune cell behavior. Their impact on immune signaling pathways is another key feature of MSCs in immunomodulatory function [17], which is explained with more detail below:

3.1.1 Cell-to-cell contact mechanisms

Direct contact between MSCs and immune cells allows interaction through cell surface molecules. MSC expression of indoleamine 2,3-dioxygenase (IDO) depletes the amino acid tryptophan locally, which inhibits T cell proliferation and activation while promoting Treg cell development [18]. Upregulation of programmed death ligand 1(PD-L1) engages with programmed cell death protein 1 (PD-1) on T cells, hindering their activation and inducing apoptosis. Fas ligand (FasL) expression carried out apoptosis of activated T cells through the Fas receptor, diminishing T cell responses [19]. Additionally, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) augmentation enables outcompeting co-stimulatory molecules on antigen-presenting cells (APCS) for binding, interrupting signals necessary for T cell activation [20]. Collectively, these membrane-bound pathways facilitate MSC modulation of multiple localized immune cell subsets.

3.1.2 Soluble factor-mediated mechanisms

MSCs demonstrate potent immunomodulation by secreting a diverse array of soluble factors like cytokines, chemokines, growth factors and EVs. These factors act autonomously and on neighboring cells to shape immune responses. Transforming growth factor-beta (TGF-β) released from MSCs strongly suppresses immunity, affecting T cell activity, regulatory T cell development, and natural killer/dendritic cell function. Prostaglandin E2 (PGE2) similarly governs T cell behavior and Treg amplification while transitioning the cytokine profile to anti-inflammation [21]. Interleukin-10 (IL-10) blocks proinflammatory cytokine generation and bolsters Treg cell’s function. Hepatocyte growth factor (HGF) impacts T cell proliferation/dendritic cells and enables repair [22]. EVs such as exosomes transport molecules like TGF-β, PGE2, and IL-10 between MSCs and immune cells to regulate recipient responses. Collectively, these secreted components downscale excessive immune activation through coordinated suppression of proinflammatory signaling and augmentation of regulatory networks [23].

3.1.3 Modulation of immune signaling pathways

MSCs wield robust immunoregulation by targeting major networks governing immune initiation and inflammation. Precisely adjusting these pathways optimizes immune balance:

• Nuclear factor-kappa β (NF-κβ) signaling coordinates proinflammatory reactions. MSCs curb and dampens inflammatory triggers, shielding tissues from collateral harm [24].

• The Janus kinase-signal transducer/activator of transcription (JAK-STAT) cascade strengthens cytokine and growth factor signaling, impacting immune effectors. MSCs suppress JAK-STAT transmission, soothing inflammatory mediator synthesis, and immune cell behavior globally [25, 26].

• Toll-like receptor (TLR) engagement alerts cells to microbe detection, kicking off innate activation. MSCs deter TLR relay, easing downstream proinflammatory cytokine induction. This directly confronts inflammatory triggers at multiple receptors [27].

• Notch intercellular communication decides cell identity crucial for immune cell development. MSCs interact with Notch receptors on immune targets, steering differentiation toward regulatory phenotypes through guided differentiation [28].

• Additional influenced pathways include Wnt/β-catenin signaling hindered by MSCs. This pathway promotes survival but also proinflammatory cytokine synthesis when awry. Via multiple membrane and exosome proteins, MSCs achieve these functional suppressions [29].

Yet, studies showed MSC groups vary quantitatively in immune regulation strength and evasion depending on the source. For example, a study contrasting bone marrow and fat tissue MSCs found fat MSCs exerted stronger, less immunogenic effects. When exposed to low interferon-gamma (IFN-γ), fat MSCs made higher IDO versus bone marrow MSCs. Activated fat MSCs also exhibited lower HLA-DR and higher CD55 [30]. These enabled more efficient immune bypasses. Following activation, fat MSCs better halted T cell proliferation than bone marrow MSCs. In contrast, bone marrow MSCs suppressed natural killer cell proliferation more [30]. Another study assessed BM, fat, and Wharton’s jelly MSC (WJ-MSC) immunomodulation – a co-culture combined each MSC type with immune cells, where fat MSCs most potently hindered proliferation. Additionally, WJ-MSCs uniquely failed to curb activated B cell and NK cell multiplication [1].

3.2 Tissue repair and regenerative potential of MSCs

Tissue damage and degenerative diseases are major health challenges worldwide, necessitating the development of innovative therapeutic strategies. MSCs, found in various tissues, hold great promise for tissue repair and regeneration [31]. In this section, we will discuss the role of MSCs in tissue repair in the context of different diseases.

3.2.1 Musculoskeletal disorders

Research shows MSCs demonstrate excellent potential for treating musculoskeletal disorders like osteoarthritis, tendon injuries, and bone breaks. In osteoarthritis, MSCs can mature into cartilage cells and promote repair. Additionally, their immunomodulation helps reduce inflammation and pain from joint degeneration [32]. For bone defects, MSCs aid regeneration by maturing into bone-forming cells and boosting the recruitment of other formative cells. They also play a pivotal role in remodeling the extracellular matrix (ECM), which is vital for repairing such conditions. MSCs make and secrete ECM constituents such as collagens, proteoglycans, and glycosaminoglycans. By synthesizing and depositing these ECM components, MSCs fortify repaired musculoskeletal tissue structure and functionality [7].

3.2.2 Cardiovascular disorders

Research shows MSC-based therapies hold promise for heart conditions like heart attack and clogged arteries. MSCs encourage new blood vessel growth by releasing an array of pro-angiogenic factors including vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), insulin-like growth factor (IGF), and hepatocyte growth factor [8]. These stimulate endothelial cell proliferation, migration, and tube formation, vital steps in blood vessel formation that aid angiogenesis in cardiovascular disease. MSCs may also decrease scar tissue and improve heart function by secreting anti-fibrotic factors. They secrete substances inhibiting extracellular matrix component formation, especially collagen, contributing to scars. These include HGF and Matrix metalloproteinases (MMPs) that can degrade excess collagen plus TGF-β blockers [33]. Additionally, MSCs can govern fibroblast and highly contractile myofibroblast behavior, which contributes to scar tightening. Released factors inhibit fibroblast activation, proliferation, and transitioning to myofibroblasts. This activity regulates scar formation. MSCs can also mature into endothelial and smooth muscle cells, assisting cardiac repair [34].

3.2.3 Neurological disorders

Neurological issues like stroke, spinal cord injury, and neurodegenerative diseases have limited treatment due to the nervous system’s low regenerative capacity. MSCs can develop into neural cells such as neurons, astrocytes, and oligodendrocytes. Administered to the central nervous system (CNS), MSCs integrate damaged areas, replacing lost or nonfunctional cells to promote repair and regrowth. They secrete various neurotrophic factors including brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and glial cell line-derived neurotrophic factor (GDNF) supporting existing neuron survival and growth [35]. These stimulate brain angiogenesis and new neural connections. MSC-secreted neurotrophins enhance neuronal survival and functional recovery. MSCs also possess immunomodulation, curbing inflammatory responses in the central nervous system by inhibiting microglia and T cell activation/proliferation and cytokine production. Reducing neuroinflammation favors neural recovery while decreasing secondary neuron damage. Moreover, MSCs activate resident brain stem and progenitor cells, aiding their maturation into functional neurons or other neural cells to boost endogenous repair mechanisms, contributing to neuronal recovery and tissue restoration [36].

By governing glial cell behavior and transitioning them to a more protective phenotype, MSCs assist inflammatory regulation, lessen glial scar formation, and build a supportive environment for neuronal survival and repair. These properties make them attractive candidates for treating neurological disorders and spinal cord injuries [37].

3.2.4 Autoimmune disorders

MSCs have a powerful ability to modulate immune responses, making them beneficial for treating conditions caused by abnormal immune activation like GVHD, COVID-19, and inflammatory bowel disease (IBD). MSCs can dampen disproportionate immune reactions, balance proinflammatory and anti-inflammatory cytokine levels, and spur tissue healing by adjusting the local microenvironment [38]. MSCs have the adaptability to evolve into various cell types, including mesodermal derivatives such as fat, cartilage, and bone cells, plus non-mesodermal varieties including nerve and liver cells. In autoimmune diseases where tissue is harmed, MSCs can mature into specific cell types needed for repair and regrowth [39]. For example, in an autoimmune arthritis, MSCs can become cartilage cells to further mend cartilage. In autoimmune liver conditions, MSCs can evolve into liver cells to facilitate organ regrowth [40].

Table 1 shows a summary of the therapeutic application of MSCs in the mentioned diseases in some clinical trials.

Disease’s category	Disease	Trial phase	Sample size	MSC source	MSC dose	Main outcome	Ref
	Osteoarthritis	Phase I/II	15	BM-MSCs	40.9 × ${10}^6$ ± 0.4$\times {10}^6$	Significant improvement in parameters including bodily pain, physical role, and physical functioning	[41]
Musculoskeletal disorders	Bone defects	phase IIa	18	BM-MSCs	15 ± 4.5 × ${10}^6$	Significant clinical improvement in patients.	[42]
	Lateral epicondylosis	Pilot study	6	AD-MSCs	${10}^6$ or ${10}^7$ cells	Significant decrease in patients’ VAS & increase in elbow performance scores	[43]
	Severe ischemic heart failure	Phase II	60	BM-MSCs	NM	Significant improvement in myocardial function	[34]
Cardiovascular diseases	Myocardial infarction	Phase II	116	WJ-MSC	6 × ${10}^6$ cells	Significant improvement in LVEF, and the myocardial viability (PET) and perfusion within the infarcted territory (SPECT) was observed.	[44]
	Ataxia	NM	24	UC-MSCs	1 × ${10}^6$ cell/kg BW	Improvement in patient’s movement and quality of life with delay in desease progression.	[45]
Neurological disorders	ALS	Phase I/II	15	BM-MSCs	1 × ${10}^6$ cell/kg BW	Improvement in patient’s status, ALS-FRS & FVC	[36]
	MS	Phase I/II	160	BM-MSCs	1–2 × ${10}^6$ cell/kg BW	MSC transplantation was safe and well tolerable by patients and showed improvement in EDSS score.	[46]
	MSA	Phase I/II	24	AD-MSCs	Two doses (1 × ${10}^7$ and 1 × ${10}^8$ cell/kg BW)	Significant decrease in the rate of disease progression (UMSARS)	[47]
	Refractory luminal Crohn’s disease	Phase I	10	BM-MSCs	1–2 × ${10}^6$ cell/kg BW	Significant decrease in patient’s CDAI	[48]
Autoimmune diseases	COVID-19	Phase I	20	UC-MSCs	1 × ${10}^6$Cell/kg BW	Improvement in patient’s oxygenation and significant decrease in CRP and inflammatory cytokines	[49, 50]
	GVHD	NM	11	BM-MSCs	NM	Significant decrease in TH17 cells, but increase in Treg cells and a shift toward TH2-cell responses	[51]

Table 1.

Therapeutic application of MSCs in various disorders.

Abbreviations: MSC, Mesenchymal stem cells; BM-MSCs, Bone Marrow derived Mesenchymal stem cells; AD-MSCs, Adipose-derived Mesenchymal stem cells; WJ-MSC, Wharton’s jelly-derived mesenchymal stem cells; VAS, patients’ visual analog scale; UC-MSCs, Umbilical cord-derived Mesenchymal stem cells; LVEF, Left Ventricular Ejection Fraction; ALS, Amyotrophic Lateral Sclerosis; MSA, Multiple System Atrophy; UMSARS, Unified Multiple System Atrophy Rating Scale; MS, Multiple sclerosis; EDSS, Expanded Disability Status Scale; GVHD, Graft-versus-host disease; CRP, C-reactive protein; CDAI, Crohn’s disease activity index; TH17, T helper 17; Treg, T regulatory cell; NM, Not Mentioned.

4. MSCs and exosomes

MSCs have been extensively studied in clinical trials due to their diverse roles including tissue repair, anti-inflammation, immunosuppression, and neuroprotection. Initially, it was believed that MSCs traveled to injury sites, differentiated, and replaced damaged cells. However, later research showed MSC engraftment and differentiation at injuries is brief and limited [52, 53]. Current research suggests MSCs mainly act through secreting trophic factors. Some propose exosomes mediate MSC cell communication as they are abundantly secreted by MSCs [54].

Exosomes are tiny lipid bilayer vesicles formed through endocytosis and budding from late endosomes, released when multivesicular bodies fuse with the plasma membrane. They release from various cells including plasma, breast milk, serum, and cerebral fluid (CSF) under inflammation, disease, or immune imbalance [6, 55]. Exosomes have potential to treat infections like COVID-19, cancers, and neurodegeneration supported by evidence. Originally discovered in the 1980s studying sheep blood cell maturation, exosomes garnered attention as key communicators [56]. Though believed to dispose of proteins, exosomes stimulate immunity in vivo and in vitro, secreting from nearly all body cells found in fluids affecting lung, kidney, and liver functions [57, 58].

Exosomes uniquely carry a diverse cargo of lipids, proteins, DNAs, and RNAs specific to their cellular origins, regulating immunity and communication, unlike other extracellular vesicles. Exosomes are characterized by membrane proteins, such as Alix, TSG101, Rab5, Rab27a, Rab27b, and multiple tetraspanins (CD37, CD63, CD81, and CD82), distinguishing them from apoptotic bodies [59]. Exosomal mRNA or miRNA transported from donor cells may alter recipient cell fates. For example, brain cancer or regulatory immune cell exosomes impacted recipient cells [59, 60]. Figure 1 schematically illustrates MSC exosome structures, contents, and target cells.

Figure 1.

Biogenesis, release, and uptake of exosomes (the figure is created using Adobe illustrator 2019).

MSC exosomes are considered MSCs’ paracrine effectors with comparable functions to MSCs. For instance, both alleviated neuroprotection and endotoxin-induced lung injury [61]. MSC exosomes contained miR-16 downregulating VEGF similarly to MSCs [62]. MSC exosomes express MSC antigens and adhesion molecules such as CD29, CD44, and CD73. Moreover, like MSCs, MSC exosomes contain genetic information for signaling pathways [63, 64].

5. Challenges and limitations in MSC therapy

There are currently some obstacles tied to using stem cells for medical functions because the way transplanted cells act is not fully decoded. Still, comprehending stem cell traits, behavior, and mechanisms more profoundly could facilitate customized treatments for many sicknesses. Before meshing stem cells with recipient tissues for lifelong gains, certain crucial points demand prudent consideration. More knowledge about stem cell properties may eventually alleviate the challenges of applying them therapeutically, leading to improved prognosis and quality of life [65].

5.1 Heterogeneity and inherent differential potency of MSCs

MSCs used for medical purposes can originate from either the patient (autologous) or a donor (allogeneic). These cells inhabit complex biological systems in the body and have diverse subpopulations. Ignoring this heterogeneity is a primary reason cell-based therapies have inconsistent results. Stem cells intrinsically proliferate indefinitely while maintaining an undifferentiated state when environmental conditions permit. Thus, appropriate signaling from adjacent cell types and local microenvironments is required for proper functioning. Variations in how cells signal to each other or respond to their surroundings can alter functional pathways. A thorough understanding of diversity across cell populations and their characteristics is essential for developing well-designed clinical trials. As such, fully considering a stem cell’s innate properties when selecting candidates for specific therapies is crucial [66, 67].

5.2 Heterogeneity of disease progression

Carefully reviewing disease worsening over time is pivotal for cell therapy success and demands serious attention. Such review informs customized remedies for enduring impacts. A thorough understanding of illness details, especially for degenerative conditions, allows individual care. Induced pluripotent stem cells (iPSCs) offer game-changing ways to model human sicknesses, particularly genetic ones, by developing iPSCs from uncommon and prevalent disease patients. This provides invaluable disease modeling and medication development, letting progression study and disorder remedies. This process enhances comprehension of underlying molecular drivers as most maladies contain numerous intertwined subsets rather than single illnesses. Initially, stem cell use may concentrate on an affliction, then an individual, potentially ushering a more targeted therapy approach. However, early efforts involve trial and error that markedly improves over time [65, 68].

5.3 Homing and targeted MSC delivery

Stem cells prove highly effective in cell therapy due to sensing their surroundings via cytokine receptors, permitting migration toward damaged tissues or tumors by chemokine gradient trails. This innate navigation aids targeted delivery for enhanced treatment. Beyond natural locating traits, induced direction strategies developed encourage further precise transportation. Methods alter cells through membrane receptor swaps, lipid particles conveying customized cells, viral vectors transmitting genes, or antibody/peptide-hooked particles delivering targets. Still, just a small fraction embeds at wished spots, and engraftment relies on administration technique. Therefore, transportation optimization can emerge from route suitability consideration, physiological forces concentrating cells, preconditioning, and transgenes actuating homing expertly. Additional efforts are required to enhance the understanding and utilization of stem cell manipulation and targeted tissue environments in order to effectively leverage these techniques, either independently or in combination, to provide optimal healthcare outcomes [65, 69, 70].

5.4 Complexity of mechanism of action of cell therapy

When exploring new treatments, a key challenge lies in understanding intricate biochemical and physiological events during application. Animal models often study such processes pre-human use. Cell therapies proved workable clinically, relying on safe, reproducible advantages. Basically, therapy forestalls or reverses sickness worsening. Both approaches overlap and differ at the technique level for cell-based remedies, necessitating customizing to meet illness-specific demands. Identifying diverse biotherapeutics such as anti-death, immune modulation, anti-scarring, pro-vessel growth, cell-cell signaling chemotaxis, local stem/progenitor growth, and diversification aspect discharge is daunting. Defining biochemical pathways and intermolecular machinery involved in cell therapy is critical to grasping stem cell behavior/roles better, a compelling cell therapy platform necessity to heighten predictive abilities. Further exploration embracing cell intricacy centers on understanding underlying behavior/roles [65, 71, 72].

6. Future directions

MSC therapies hold tremendous promise for regenerative medicine, but their complete potential can be realized by implementing various techniques and approaches to reduce adverse effects and improve treatment outcomes. One strategy is the genetic engineering of MSCs, which permits precise modifications to their genetic makeup in order to enhance their therapeutic properties. By introducing specific genes into MSCs, it is possible to improve their survival, ability to differentiate into desired cell types, promote tissue repair, modulate the immune response, or secrete therapeutic factors. This genetic engineering can be achieved through methods such as viral vectors, non-viral vectors, or genome editing tools like CRISPR-Cas9, ensuring targeted and efficient modification of MSCs [73, 74].

Furthermore, the utilization of MSC-derived products, such as exosomes and EVs, has emerged as a promising approach to augment the therapeutic effects of MSC therapies. These vesicles contain a diverse array of bioactive molecules, including proteins, nucleic acids, and signaling molecules that can exert potent therapeutic effects by facilitating intercellular communication, promoting tissue regeneration, and reducing inflammation [75]. To boost the efficacy of MSC-derived products, various techniques can be employed, including optimization of isolation procedures, standardization of production protocols, and characterization of cargo contents. Additionally, engineering MSCs to enhance the secretion of specific exosomes or EVs with desired therapeutic cargo can further enhance their therapeutic potential.

Besides, to mitigate adverse effects associated with MSC therapies, careful consideration should be given to factors such as cell dose, route of administration, and patient selection. Optimizing the dose of MSCs administered ensures that the therapeutic effects are maximized while avoiding potential complications. Choosing the appropriate route of administration, whether it be systemic, local, or targeted delivery, can enhance the homing and engraftment of MSCs to the desired tissue, improving treatment efficacy. Moreover, thorough patient evaluation and selection based on disease characteristics, immune compatibility, and pre-existing conditions can help minimize adverse reactions and maximize the safety and effectiveness of MSC therapies. Continued research and advancements in these areas will undoubtedly contribute to unlocking the full therapeutic potential of MSC-based therapies and pave the way for transformative regenerative medicine.

7. Conclusion

In summary, MSCs possess unique properties making them highly beneficial for therapeutic applications. Their ability to self-renew, differentiate into various cell types, and modulate immunological responses provide MSCs with regenerative capabilities across multiple organ systems. Extensive research over the past decades has revealed the therapeutic potential of MSCs and their exosomes for treating a wide range of medical conditions. As the introduction described, MSCs have shown promise in orthopedic applications like bone and cartilage repair. They have also been studied for their cardiovascular benefits in improving heart function and promoting blood vessel growth. Perhaps most importantly, MSC therapies have demonstrated encouraging results in central nervous system disorders as well as autoimmune and inflammatory conditions.

Looking ahead, further research is still needed to optimize isolation and culture methods to standardize MSC production. Additional pre-clinical and clinical studies are also required to fully characterize MSC engraftment, bio distribution, and mechanisms of action in vivo. Despite these remaining challenges, MSCs represent a promising tool for regenerative medicine. Their multipotency and immunomodulatory properties provide a versatile cell-based therapeutic approach with potential applications across many areas of human disease. With continued advances in basic and translational research, MSC therapies may transform patient care and management of conditions currently lacking effective medical solutions.

Acknowledgments

We thank all those who have directly and indirectly helped in writing this chapter.

Conflict of interest

The authors declare no conflict of interest.