Unveiling Mesenchymal Stem Cells’ Regenerative Potential in Clinical Applications: Insights in miRNA and lncRNA Implications

It is now widely recognized that mesenchymal stem cells (MSCs) possess the capacity to differentiate into a wide array of cell types. Numerous studies have identified the role of lncRNA in the regulation of MSC differentiation. It is important to elucidate the role and interplay of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) in the regulation of signalling pathways that govern MSC function. Furthermore, miRNAs and lncRNAs are important clinical for innovative strategies aimed at addressing a wide spectrum of existing and emerging disease. Hence it is important to consider their impact on MSC function and differentiation. Examining the data available in public databases, we have collected the literature containing the latest discoveries pertaining to human stem cells and their potential in both fundamental research and clinical applications. Furthermore, we have compiled completed clinical studies that revolve around the application of MSCs, shedding light on the opportunities presented by harnessing the regulatory potential of miRNAs and lncRNAs. This exploration of the therapeutic possibilities offered by miRNAs and lncRNAs within MSCs unveils exciting prospects for the development of precision therapies and personalized treatment approaches. Ultimately, these advancements promise to augment the efficacy of regenerative strategies and produce positive outcomes for patients. As research in this field continues to evolve, it is imperative to explore and exploit the vast potential of miRNAs and lncRNAs as therapeutic agents. The findings provide a solid basis for ongoing investigations, fuelling the quest to fully unlock the regenerative potential of MSCs.


Introduction
Mesenchymal stem cells (MSCs) are multipotent cells that can differentiate into a variety of cell types, including bone, cartilage, muscle, and fat cells.They are commonly isolated from bone marrow but can also be found in other tissues, such as adipose tissue and the umbilical cord.MSCs are attractive for medical applications due to their ability to migrate to sites of injury or inflammation and their potential to differentiate into cells that can repair damaged tissue [1].In addition, MSCs have immunomodulatory properties, making them useful for treating conditions such as autoimmune disorders and graft-versushost disease.MSCs can be expanded in culture and manipulated ex vivo to promote specific cellular differentiation and are considered a promising tool for regenerative medicine [2].However, further research is needed to fully understand the mechanisms underlying MSC function and to optimize their use for various clinical applications.
MicroRNAs (miRNAs) are small, non-coding RNA molecules that play a critical role in the regulation of gene expression.miRNAs bind target messenger RNA (mRNA) molecules, leading to their degradation or inhibition, preventing them from being translated into proteins [3].This allows miRNAs to regulate the expression of multiple genes, making them an important component of gene regulation and cellular function.miRNAs have been shown to play a key role in regulating gene expression, and to be involved in a wide range of biological processes, including development, cell growth and division, and apoptosis [4][5][6][7].miRNAs have also been implicated in the development and progression of various diseases, including cancer, cardiovascular disease, and neurological disorders [8][9][10].By regulating the expression of genes involved in disease, miRNAs can act as either oncogenes or tumour suppressors [11][12][13][14].
The involvement of miRNA in a multitude of diseases makes them potential biomarkers for diagnostics as well as therapeutic tools, targeting genes responsible for a specific condition [15][16][17] Furthermore, miRNAs play a crucial role in regulating MSC differentiation into various cell types, such as bone and cartilage [18,19].MSCs can secrete miRNAs that promote or inhibit the differentiation of neighbouring cells [20].The regulation of miRNAs in MSC differentiation is complex, and the role of specific miRNAs in the process is still being elucidated.
miRNAs exert a crucial influence on the intricate regulation of MSCs.Notably, certain miRNAs have been identified as key regulators of the immunosuppressive properties possessed by MSCs, underscoring their significance in unlocking the full therapeutic potential of these cells [21,22].By introducing specific miRNAs into MSCs, researchers can target and tailor their therapeutic effects for specific diseases or conditions [23,24].For instance, engineering MSCs to express anti-inflammatory miRNAs holds promise for combating inflammatory diseases, while harnessing miRNAs that promote tissue repair could revolutionize the treatment of tissue injuries [25,26].This intersection of miRNAs and MSC engineering offers a promising frontier for advancing regenerative medicine and personalized therapeutic interventions.
Long non-coding RNAs (lncRNAs) are RNA molecules that are longer than 200 nucleotides but do not encode proteins [27,28].Unlike protein-coding mRNA, lncRNA do not have a conserved open reading frame and are not translated into proteins.Despite their lack of coding capacity, lncRNA play critical roles in gene regulation and cellular processes.They have been shown to act as epigenetic regulators, scaffolds for protein complexes, and decoys for miRNA, among other functions [29][30][31][32][33]. lncRNA can also serve as molecular markers for various diseases, including cancer, and can be used for diagnostic and prognostic purposes [34][35][36].The discovery of lncRNA has expanded our understanding of the diversity and complexity of RNA-mediated gene regulation and has opened up new avenues for the development of therapeutic strategies [37].However, much remains to be learned about the full extent of lncRNA functions and the mechanisms underlying their effects on gene expression [38,39].
A number of studies have identified lncRNA as playing a key role in regulating MSC differentiation into various cell types [40,41].For example, the lncRNA HOTAIR has been shown to regulate the differentiation of MSCs into osteoblasts [42].In addition, the lncRNA MALAT1 has been shown to promote the ability of MSCs to form new blood vessels and promote proliferation [43].Studies have highlighted the potential application of lncRNAs as innovative biomarkers for diagnosis and as potential targets for therapeutic treatments [44][45][46].

Characteristics and Function of MSCs
MSCs are a type of stem cell that have the ability to differentiate into a variety of cell lines, including bone, cartilage, muscle, and fat cells.They are commonly isolated from bone marrow, but they can also be found in other tissues, such as adipose tissue and umbilical cord (Figure 1) [47][48][49].MSCs exhibit a range of characteristic properties, which enable their identification, as well as facilitate the range of their physiological functions (Figure 1) [50].MSCs are characterized by specific cell surface markers such as CD73, CD90, and CD105, and lack the expression of hematopoietic cell markers like CD45, CD34, and CD14.These markers are used to identify and isolate MSCs from other cell types [51].Moreover, there is a number of characteristic properties, that further allow to identify MSCs among other stem cell populations (Figure 2).MSCs are characterized by their multipotency, which means that they have the ability to differentiate into multiple cell types, including osteocytes, chondrocytes, adipocytes, and myocytes [52,53].MDC differentiation potential makes them an important tool for regenerative medicine and tissue engineering [2].The process of MSC differentiation is regulated by a variety of factors, including growth factors, cytokines, and the extracellular matrix.Differentiation involves a series of molecular events that result in changes in gene expression and cell morphology.MSC differentiation can be induced by specific factors, such as dexamethasone, ascorbic acid, and beta-glycerophosphate for osteogenic differentiation, transforming growth factor-beta (TGF-beta) and bone morphogenetic protein-2 (BMP-2) for chondrogenic differentiation, and insulin and dexamethasone for adipogenic differentiation [53,54].Osteogenic differentiation is the process by which MSCs differentiate into osteoblasts, which are cells responsible for bone formation.During osteogenic differentiation, MSCs undergo changes in gene expression and cell morphology that result in the production of bone matrix proteins, such as collagen and osteocalcin.The resulting osteoblasts then mineralize the bone matrix to form new bone tissue [55,56].Chondrogenic differentiation is the process where MSCs differentiate into chondrocytes, which are cells responsible for cartilage formation.During chondrogenic differentiation, MSCs undergo changes in gene expression and cell morphology that result in the production of cartilage matrix proteins, such as collagen and aggrecan [57,58].The resulting chondrocytes then produce a cartilage matrix that can be used for tissue engineering applications [58].Adipogenic differentiation is the process in which MSCs differentiate into adipocytes, which are cells responsible for fat storage [59].During adipogenic differentiation, MSCs undergo changes in gene expression and cell morphology that result in the production of lipid droplets.The resulting adipocytes can be used for tissue engineering applications, such as the development of adipose tissue for reconstructive surgery [60,61].Finally, myogenic differentiation is the process where MSCs differentiate into myocytes, which are cells responsible for muscle formation [62,63].During myogenic differentiation, MSCs undergo changes in gene expression and cell morphology that result in the production of myogenic proteins, such as MyoD and myogenin.The resulting myocytes can be used for tissue engineering applications, such as the development of muscle tissue for reconstructive surgery [64].
Furthermore, MSCs have the ability to self-renew, which means that they can freely proliferate to create the exact copies of themselves in an almost indefinite manner.This ability is essential for the maintenance of a pool of MSCs in the body that can be used for tissue regeneration and repair when needed.Self-renewal is a complex process that involves several mechanisms.One of the key factors involved in self-renewal is the expression of specific genes that regulate stem cell function.In MSCs, the expression of genes such as Sox2, Oct4, and Nanog has been found to be important for self-renewal [65,66].The process of self-renewal is strongly influenced by growth factors and cytokines, as they play a crucial role in signaling mesenchymal stem cells (MSCs) to retain their stem cell characteristics and undergo division, resulting in the generation of additional stem cells [67][68][69][70].For example, fibroblast growth factor-2 (FGF-2) is important for the self-renewal of MSCs [69,71].The extracellular matrix (ECM) is a complex network of proteins and other molecules that surrounds cells and provides structural support which plays an important role in MSC self-renewal [72].Interactions with the ECM modulate MSCs' behaviour, including their self-renewal capacity.Notably, a laminin peptide, an ECM molecule, has been identified as a promoter of MSC self-renewal [73].Finally, the microenvironment, or niche, where MSCs reside, plays a crucial role in their self-renewal.Within this niche, MSCs receive specific signals that govern their behaviour, including the capacity to self-renew.For instance, The hypoxic microenvironment is crucial for maintaining undifferentiated MSCs by keeping them quiescent and promoting necessary self-renewal.Hypoxia inducible factor (HIF) acts as a molecular regulator within this environment, controlling MSC differentiation and survival [74].
Moreover, MSCs have immunomodulatory properties, they can regulate the various elements of the immune system.They can suppress the activity of T-cells and other immune cells, reducing inflammation and preventing immune-mediated tissue damage [75].MSCs can aid in tissue repair and regeneration by secreting factors that promote the growth and activity of immune cells and anti-inflammatory factors that can reduce inflammation and promote tissue repair [76].These factors include interleukin-10 (IL-10), transforming growth factor-beta (TGF-β), and prostaglandin E2 (PGE2) [77,78].MSCs can also secrete factors that promote the growth of new blood vessels, a process known as angiogenesis.This function can play an important role in in repairing damaged tissues that require a new source of blood supply [79,80].Furthermore, MSCs have been shown to have neuroprotective properties, meaning they can protect neurons from damage and promote their survival [81].They can secrete factors that promote nerve cell growth and regeneration, making them a potential therapy for neurological disorders [82].MSCs can also promote wound healing by secreting growth factors that promote the growth of new skin cells and blood vessels [83,84].Finally, MSCs are able to remodel the extracellular matrix (ECM) of tissues.The ECM is the complex network of proteins and other molecules that provides structural support to tissues.MSCs can produce enzymes that break down and remodel the ECM, which is important for tissue repair and regeneration [85].
In conclusion, MSCs have a wide range of known physiological functions in the body, including tissue repair and regeneration, immune modulation, anti-inflammatory effects, angiogenesis, and neuroprotection.It also needs to be noted that these cells are a subject of continuous research, indicating that there might by a wide array of yet undiscovered functions that could bring additional promise to their application in further fields of science and medicine.

Preclinical Studies, Clinical Trials, and Therapies
Preclinical studies, clinical trials, and therapies involving mesenchymal stem cells (MSCs) are aimed at exploring the therapeutic potential of these cells in various diseases and conditions.The development of MSC-based therapies has been driven by their unique characteristics, including the ability to self-renew, differentiate into various cell types, and exert immunosuppressive effects [86].Preclinical studies are conducted in laboratory settings or in animals, and are used to evaluate the safety and efficacy of MSCs before they can be tested in humans.These studies have demonstrated that MSCs have the potential to regenerate damaged tissues, reduce inflammation, and promote tissue repair [1].MSCs have been shown to improve outcomes in preclinical models of a range of diseases and conditions, including heart disease, osteoarthritis, liver disease, and spinal cord injury, among [87][88][89].MSC-based therapies involve the administration of MSCs directly to patients with the aim of treating specific diseases or conditions.MSCs can be delivered to patients either through injections into the affected tissues or intravenously.MSCs are capable of homing to damaged tissues and promoting tissue repair through mechanisms such as secreting growth factors, reducing inflammation, and inducing angiogenesis [53,79].Clinical trials are conducted in humans to evaluate the safety and efficacy of MSC-based therapies.Clinical trials involving MSCs are currently underway in various stages, ranging from phase I to phase III.Phase I trials are usually small and focus on evaluating the safety of MSC treatments, while phase II and III trials are larger and focus on evaluating the efficacy of MSC treatments.The results of these trials have been promising, with MSCs showing the potential to treat a range of diseases and conditions, including osteoarthritis, Crohn's disease, heart failure, and spinal cord injury.The currently completed and terminated studies related to MSCs were presented in Table 1.Furthermore, according to the ClinicalTrials.govdatabase, there are 318 ongoing clinical trials related to mesenchymal stem cells, in different completion stages, with no results yet reported.
While the potential for MSCs in regenerative medicine is vast, there are still many challenges that need to be overcome.One of the major challenges is to ensure the safety and efficacy of MSC treatments, which requires rigorous preclinical and clinical testing [90].Additionally, the high cost of MSC treatments, as well as the limited availability of funding and insurance coverage, continue to be major barriers to their widespread use.
In conclusion, preclinical studies, clinical trials, and MSC-based therapies are contributing to the development of new treatments for a range of diseases and conditions.While the results of these studies have been promising, further research is needed to fully understand the mechanisms of action of MSCs and to determine their safety and efficacy in the treatment of specific diseases and conditions [90].Nevertheless, MSCs hold great promise as a new class of regenerative therapies, and their continued development and testing is essential to realizing their full therapeutic potential.

MSC Differentiation
Based on their ability to differentiate, MSCs support tissue homeostasis by acting as a source of renewable progenitor cells for the repair of damaged tissues and the replacement of cells in routine cellular turnover throughout adult life [91][92][93].When cultured under specific conditions, they can differentiate into multiple mesenchymal lineage cell types, including osteoblasts, chondrocytes, adipocytes, and myoblasts [94][95][96][97].The classical method for osteogenic differentiation of human MSCs involves incubation in fetal bovine serum (FBS)-containing medium supplemented with ascorbic acid, β-glycerophosphate, and dexamethasone, resulting in an increase in calcium accumulation and alkaline phosphatase activity [98,99].Chondrogenic differentiation is accomplished using pelleted micromass cultured in the presence of transforming growth factor (TGF)-β in serum-free medium, which produces cartilage-specific, highly sulfated proteoglycans and type II collagen [98].Adipogenic differentiation of MSCs is demonstrated through the detection of lipid vacuoles after dexamethasone, insulin, isobutyl methyl xanthine, and indomethacin are added to medium containing FBS [9].MSCs can also differentiate into myoblasts when treated with 5-azacytidine and amphotericin B, which fuse into rhythmically beating myotubes [100].Furthermore, MSCs can also give rise to cross-lineage cell types such as endodermalhepatocytes and β-cells of pancreatic islets and ectodermal-neurons, a process known as trans-differentiation [101,102].The liver cells were obtained from MSCs in two stages by culturing them in Iscove's modified Dulbecco's medium (IMDM) supplemented with HGF, bFGF and nicotinamide, and in the next stage with the addition of oncostatin M, dexamethasone, and ITS+ (insulin, transferring, selenium).Albumin, α-fetoprotein, and hepatocyte nuclear factor 4 (HNF-4) are present in the resulting cells, which are hepatocyte typical markers [103].Pancreatic islets of β-cells capable of producing insulin were obtained from MSCs by treating them with a mixture of growth factors secreted by regenerating cells of the pancreas and also by using acitin A, sodium butyrate, taurine, and nicotinamide [104,105].According to Hofstetter and colleagues, neuron-like cells differentiated from MSCs lack voltage-gated ion channels that are required for action potential generation; thus, they may not be considered as true neurons [106].Additionally, transdifferentiate of MSCs into endothelial cells expressing endothelial nitric oxide synthase have been reported that contribute to endothelial function improvement in vascular injury rat model [107,108].There has been widespread evidence that miRNAs and lncRNAs play an important role in the differentiation of MSCs, both positively and negatively, as reported herein (Tables 2 and 3).

Signalling Pathways Governing MSC Function
Based on the widely accepted definition of 'tissue engineering' that was proposed by Robert Nerem in 1988, MSCs can be regarded as an inherent component of the modern regenerative medicine, since they can readily be used for the generation of different cell lineages.The growing success of today's regenerative medicine stems from the pluripotent nature of MSCs that renders them capable of transforming into other cell types with regards to their microenvironment, which consists of non-coding RNAs, among others [303].A strikingly high proportion of studies have focused on identification of ncRNAs that facilitate or impair the differentiation of MSCs.These ncRNAs usually constitute an elaborate network or axis of interactions involving lncRNAs, miRNAs, mRNAs and other types of ncRNAs, which can ultimately affect the proliferative and regenerative activity of these cells.Generally, in RNA-based regulatory pathways, lncRNAs bind and sponge miRNAs to indirectly promote the translation of certain mRNAs to their final product.As such, a basic lncRNA/miRNA/mRNA pathway includes an inhibitory pathway accompanied by an indirect de-repressing effect.While a range of other lncRNAs and miRNAs might be involved in this inhibitory process, they usually are the final effector molecule that determines the final cell fate [304].For instance, if the axis ends in 'vascular endothelial growth factor' (VEGF) with a net de-repressing or stimulatory effect, the MSCs occurring in that microenvironment will be compelled to differentiate into endothelial cells, giving rise to vasculature [305].In addition to microenvironmental properties, the biological origin of MSCs may influence the course of differentiation.Bone marrow, umbilical cord, adipose tissue, peripheral blood and synovium stand among the most frequently preferred sources of MSCs in experimental and clinical applications.Despite being pluripotent, MSCs are still subject to epigenetic regulatory programs associated with the source from which they are derived.In this sense, MSCs extracted from the synovial space are theoretically anticipated to yield better results when used for cartilage regeneration in joint disorders [306].Still, there are no strict rules regarding the source, as there are reports of successful trials of seemingly contrasting sources for regenerative purposes such as application of adiposederived MSCs for osteogenic regeneration in patients with osteoarthritis [307], suggesting, once again, that environmental factors and regulatory pathways are as important as the source.Figure 3 illustrates various miRNAs that are critical during MSCs differentiation.The lnRNA-miRNA basis of MSC differentiation has primarily been studied in the case of osteogenic, chondrogenic and adipogenic differentiation.More scantly, the role of ncRNAs in hepatogenic, angiogenic and lymphatogenic differentiation has also been explored, albeit, to a much lesser extent.Induction of osteogenic differentiation is of utmost importance in the treatment of degenerative bone diseases.Accordingly, regulatory lncRNAs and miRNAs can be used as therapeutic agents or targets with regards to their stimulatory or inhibitory effects, respectively.One good example is 'metastasis associated lung adenocarcinoma transcript 1 (MALAT1), a tumor-associated lncRNA with known osteogenic effects [308,309].Considering its mechanism of action, MALAT1 can either be used as an exogenous therapeutic agent for induction of osteogenesis or targeted by proxy when it is lowly expressed.Downregulation of MALAT1, as an osteogenic lncRNA, results in de-repression of anti-osteogenic miRNAs, which can be targeted and silenced using specialized short hairpin RNAs (shRNAs) [308,309].Though, differentiation is not necessarily a desirable outcome, particularly when it comes to malignancies.MALAT1, which is a beneficial factor in the case of hypoproliferative disorders, may assume an adverse role in the context of oncogenesis, where overexpression of MALAT1 stimulates formation of new endothelial cells, hence, promoting angiogenesis in osteosarcoma [310].However, the regulation of differentiation is important in treating disorders associated with impaired formation or degeneration of vasculature, which may benefit from overexpression of MALAT1 [305].One reason for this presumable divergent function of MALAT1, or any other lncRNA for that matter, is the difference in miRNAs which are targeted and sponged in each scenario.When it is a beneficial pro-angiogenic factor, MALAT1 targets miR-206 to upregulate VEGFA in the population of endothelial cells that might be overproducing the anti-angiogenic miR-206 [305].When it is an aggravator of tumor-associated angiogenesis, MALAT1 targets the anti-angiogenic miR-150-5p, when it should not be sponged [310].In this sense, a good understanding of the lncRNA-miRNA networks governing cell differentiation in health and disease can substantially contribute to the performance of regenerative medicine.The full overview of knowledge regarding the participation of miRNAs and lncRNAs in differentiation of MSCs, as well as the different lncRNA-miRNA axes regulates differentiation into different lineages (Table 4).

Practical Implications and Future Perspective of lncRNA and miRNA in MSCs Treatment
Numerous studies highlight the potential of mesenchymal stem cells (MSCs) in repairing various organs like the lungs, heart, and skin.Exosomes, tiny vesicles produced by MSCs, have gained importance in regenerative medicine [335].Exosomes, packed with RNA and proteins, are safer and more stable than direct MSC transplants [336].They play a crucial role in healing by delivering therapeutic substances, especially microR-NAs (miRNAs), which regulate gene activity in nearby or distant cells [337].Studies show that MSC-derived exosomes can transport miRNAs, such as miR-132-3p, to endothelial cells, improving their growth and reducing blood-brain barrier dysfunction in a brain injury model [338].These exosomes boost the expression of essential genes in traumatic brain injury.
Exosomes and miRNAs offer promise in treating various diseases, including neurological, cardiovascular, and kidney disorders.Exosomes containing specific miRNAs have beneficial effects on neurological conditions, reducing cell death and inflammation.MiR-NAs like miR-126 and miR-184 help brain recovery in stroke models [339].In autoimmune encephalomyelitis, BM-MSC exosomes deliver miR-367-3p, reducing symptoms [340].MSC-derived exosomes are also promising in cardiovascular diseases.They target specific genes, reducing inflammation and improving heart function.For example, exosomes containing miR-149 have been used to target genes and modulate the inflammatory response [341].In kidney repair, they counter calcification and promote recovery.Exosomes containing miR-874-3p have been shown to control necroptosis, decrease renal tubular cell damage, and improve healing in acute kidney injury [342].For liver issues, exosomes enriched with miR-148a mitigate symptoms, and miR-20a-5p promotes liver repair [343,344].Lung diseases, arthritis, and osteoarthritis also show potential for exosome therapy.Lung diseases, such as cystic fibrosis, pulmonary fibrosis, and radiation-induced lung injury, have been studied in the perspective of exosomal therapy.MiR-466f-3p and miR-186 have shown therapeutic potential in reducing inflammation, fibrosis, and promoting repair [345,346].In the case of rheumatoid arthritis, exosomes containing miR-150-5p have been used to downregulate MMP14 and VEGF, reducing inflammation and protecting against cartilage and bone degradation [347].Exosomes can be used to encourage direct intracellular transfer of miRNAs between cells, thereby promoting anti-inflammatory effects.Osteoarthritis has been studied in the context of BMP2-induced chondrogenesis and the Wnt signaling pathway.Exosomal miR-181c-5p and miR-92a-3p have been implicated in cartilage repair and Wnt inhibition [348,349].
LncRNAs have shown exciting potential in addressing various health conditions and guiding MSCs through various cellular processes.In osteogenic differentiation, LncR-NAs like H19, HULC, and MALAT1 exert their influence, promoting bone formation through mechanisms involving miRNAs and key signaling pathways [279,286,287].Notably, researchers have uncovered a distinctive LncRNA, lncRNA-OG, driving bone growth alongside hnRNPK, which could pave the way for better bone-related treatments [289].While the immunoregulatory potential of MSCs is significant, only a few studies, like one involving LncRNA-MALAT1, have delved into this arena [43].Investigating LncRNAdriven immune regulation in MSCs is an area rich in potential.Furthermore, LncRNAs including Lnc-ZNF354A, Lnc-LIN54, Lnc-FRG2C, and Lnc-USP50, were found to be closely associated with pathological bone formation in ankylosing spondylitis [350].Adipogenic differentiation, the process of forming fat cells, is also influenced by LncRNAs such as GAS5 and HOTAIR [299,300].The balance between osteogenesis and adipogenesis in MSCs is delicately controlled by LncRNAs like H19 and TCONS_00041960, offering a potential therapeutic angle for conditions like osteoporosis [292,296].Interestingly, LncRNA lnc13728 surfaces, significantly influencing the proliferation of fat cells and modulating genes associated with obesity, presenting opportunities to tackle obesity-related challenges more effectively [298].In the context of chondrogenic differentiation, LncRNAs like ZBED3-AS1 steer MSCs toward the formation of cartilage tissue, influencing pivotal pathways such as Wnt/β-catenin and offering prospects for therapeutic interventions, particularly in condi-tions like osteoarthritis [295].Venturing into the realms of neurogenesis, myogenesis, and endothelial differentiation, LncRNAs like H19, MIAT, MEG3, and HULC actively contribute to the formation of neural, smooth muscle, and endothelial cells [351,352].Their roles in addressing nerve injuries and cardiovascular therapies beckon for deeper exploration.
Meanwhile, the impact of exosomes from lung cancer on the LncRNA expression profile of MSCs emphasizes the participation of LncRNAs in the intricate interplay between MSCs and tumor cells, ultimately affecting the progression of diseases [353].This underscores the potential of using LncRNA profiles in circulating MSCs as personalized diagnostic tools for specific medical conditions.Circulating MSCs in peripheral blood hold promise as diagnostic markers for various diseases, offering a novel and precise diagnostic method by identifying specific LncRNAs or patterns within these MSCs.Furthermore, there is an uncharted frontier in enhancing the clinical effectiveness of MSC-based therapies by manipulating LncRNAs that govern MSC behavior.Employing gene editing techniques to fine-tune specific LncRNA expressions has the potential to enhance the immunoregulatory capabilities of MSCs in autoimmune diseases and guide their differentiation into specialized cell types for tissue and regeneration engineering.This dynamic approach opens exciting avenues for refining MSC-based therapies across various diseases.
Overall, LncRNAs are master conductors of MSC behavior, orchestrating a symphony of cellular functions, from differentiation to proliferation and immunoregulation.while, exosomes and miRNAs have opened exciting avenues in regenerative medicine, offering hope for various health conditions.Understanding and harnessing the power of LncRNAs in MSCs offer promising avenues for innovative therapeutics and regenerative medicine.

Conclusions
It is important to consider the intricate regulatory roles of miRNAs and lncRNAs in governing the signalling pathways that dictate MSC functioning and differentiation.The findings presented underscore the pivotal significance of these small RNA molecules in the realm of regenerative medicine and hold great promise for future therapeutic applications.The characterization and functional attributes of MSCs have been thoroughly examined, revealing their remarkable potential in tissue repair and immune modulation.As highlighted by an array of preclinical studies, clinical trials, and innovative therapies, MSCs have demonstrated their transformative capability in addressing diverse medical conditions, further emphasizing their significance as a regenerative resource.The emerging understanding of lncRNAs as key modulators of lineage commitment.The intricate interplay between lncRNAs and signalling pathways provides crucial insights into the mechanisms governing MSC fate determination, offering opportunities for targeted interventions and precision therapeutics.Furthermore, the regulatory impact of miRNAs on MSC differentiation has been comprehensively analysed, unravelling the complexity of gene expression network.The interplay between miRNAs and their target genes offers a deep understanding of the regulatory landscape driving MSC differentiation processes, paving the way for potential therapeutic strategies targeting these molecular interactions.
In conclusion, the knowledge amassed serves as a crucial foundation for further advancements in regenerative medicine.Harnessing the regulatory potential of miRNAs and lncRNAs in MSCs presents exciting prospects for developing targeted therapies and personalized treatment approaches, ultimately enhancing the efficacy of regenerative strategies and positively impacting patient outcomes.As research in this field continues to evolve, it is imperative to explore and exploit the vast potential of miRNAs and lncRNAs as therapeutic agents.The findings presented here provide a solid basis for ongoing investigations, fuelling the quest to fully unlock the regenerative potential of MSCs.

Figure 1 .
Figure 1.Overview of the most common MSC sources and methods of their isolation.Created with Biorender.com.

Figure 2 .
Figure 2. The overview of the identifying characteristics of MSCs.Created with Biorender.com.

Figure 3 .
Figure 3.A visual representation of miRNA participation in the process of MSC differentiation.

Table 1 .
Compilation of completed and terminated studies related to the use of MSCs, obtained from the ClinicalTrials.govdatabase.

Table 2 .
The role of miRNA in differentiation of MSCs.

Table 3 .
The role of lncRNA in differentiation of MSCs.

Table 4 .
List of lncRNA-miRNA axes regulating differentiation of MSCs into distinct cell lineages.