Mesenchymal stem cells (MSCs) are the current focus of extensive works worldwide, directed to elucidate their nature and properties, as well as to develop cell-based therapies for various diseases (Kfoury and Scadden, 2015; Harrell et al., 2019; Lerman, 2021; Zhu et al., 2021; Hoang et al., 2022). Our understanding of the therapeutic potential of MSCs has been promoted by research progresses such as the identification and characterization of MSCs from diverse origins (Darzi et al., 2016; Donders et al., 2016; Lu et al., 2016; Cooper et al., 2020; Medrano-Trochez et al., 2021), recognition of MSC contributions to organismal homeostasis and diseases (Sui B. D et al., 2016; Neri and Borzì, 2020; Sui et al., 2020; Krampera and Le Blanc, 2021; Spallanzani, 2021), the application or intervention of MSCs in tissue engineering and cytotherapy (Akiyama et al., 2012; Cassandras et al., 2020; McNeill et al., 2020), and clarification of transcription factors and signaling pathways capable of controlling the behaviors of MSCs (Feng et al., 2017; Elbaz et al., 2019; Zecchini et al., 2019; Choi et al., 2021).

Further illuminating matters, function and therapeutic efficacy of MSCs are highly regulated by the surrounding niche/microenvironment (Zhu et al., 2016; Mehrbani Azar et al., 2018; Tejero et al., 2019; Gilchrist et al., 2021), and studies on skeletal degenerative and autoimmune conditions have highlighted the essence of cell-host interplay in the forms of cell-cell contact and paracrine secretion in MSC cytotherapy (Liu S. et al., 2015; Kou et al., 2018; Li et al., 2018; Liu et al., 2018; Tejero et al., 2019; Ha et al., 2020). Interestingly, these interactions provide persistent therapeutic benefits that remain detectable long after the disappearance of transplanted MSCs (Liu S. et al., 2015; Ng et al., 2015). Therefore, there is an urgent need for a more complete understanding of the molecular mechanisms and biological processes underlying MSC therapies.

In this review, we summarize recent developments regarding the role of MSCs in a variety of disease models and provide insight into the mechanisms by which MSCs interact with endogenous stem cells to exert therapeutic effects, refining the interconnection between MSCs and cells fused or differentiated into functional cells at the site of damage in the early stages of treatment. This landscape offers a unifying explanation of how the MSC therapy re-establishes the health of the diseased organism across diverse tissues with long-lasting beneficial profiles, shedding light on the future development of cell-free and cell-targeted therapies.

The concept of MSCs originated from seminal studies performed by Friedenstein et al. who confirmed that postnatal mammalian bone marrow (BM) contains a subset of non-hematopoietic stromal cells that are both self-renewing and multipotent. Currently, the MSC concept is referred to as primitive cells capable of adherence, forming fibroblastic colonies and multilineage differentiation when cultured ex vivo (Kfoury and Scadden, 2015). MSCs, other than those derived from the BM (BMMSCs) (Jiang et al., 2002), have been shown to reside in a variety of tissues, such as the adipose (ADSCs) (Zuk et al., 2002), umbilical cord (UCMSCs) (Erices et al., 2000), tendon (TSPCs) (Bi et al., 2007), dental pulp (DPSCs) (Gronthos et al., 2000), periodontal ligament (PDLSCs) (Seo et al., 2004) and even the exfoliated deciduous teeth (SHED) (Miura et al., 2003). The surface profiles of MSCs are still not fully understood; we use a complex of heterogeneous distinct subsets of MSCs, which can be considered as a network of stromal components with interrelated and complementary in vivo capabilities in the maintenance of tissue homeostasis (Kfoury and Scadden, 2015) ( Figure 1 ). Despite recent studies on identifying functional heterogeneity and specific markers of these cells (Chan et al., 2015; Worthley et al., 2015), the ready abilities of isolation, amplification and differentiation have made MSCs an ideal subject for extensive investigation in tissue engineering and regenerative medicine (Kfoury and Scadden, 2015). Furthermore, emerging experimentation elucidating immunomodulation, tissue regeneration, anti-aging ability and in vivo biology of MSCs has prompted their potent applications in cell-based therapy (Yue et al., 2016; Carr et al., 2019; Fu et al., 2019; Yang et al., 2019). Recent experiments with MSCs have been applied to the study and treatment of COVID-19, and the rapid response to emergent diseases is evidence of the promise of MSCs in the treatment of immune and infectious diseases (Li et al., 2020; Meng et al., 2020; Abdelgawad et al., 2021; Shi L. et al., 2021).

Despite the well-documented experimentation describing the functional characteristics of MSCs, including easy access, anti-inflammatory activity mainly in the form of a thirst for damaged cells, immune modulation and regeneration promotion, a fundamental issue concerns the identity and physiological function in vivo ( Figure 1 ). However, studies in this field have been hampered by a lack of MSC-specific antigens that permit both prospective identification and fate mapping. According to the latest statistic, it is estimated that > 9233 clinical trials have been registered and conducted on MSCs, but the lack of adequate standardized methods to assess the main safety issues involved in MSCs, specifically the lack of MSC-specific antigens for prospective identification and fate localization, has hindered their use in clinical settings. Until recently, lineage tracing and ablation studies identified several surface markers representing subsets of MSCs related to their respective nature and niches. In particular, regarding the ability of MSCs to trigger and promote tumorigenesis, although few studies have supported that MSCs are relatively safe for clinical use, the same MSCs applied to other receptors or tissues and organs also require further discussion and study.

The developmental origin and function of MSCs remain an active area of research. Although it was originally believed that MSCs (particularly BMMSCs) are derived from the mesoderm and give rise to mesenchymal cells, such as osteoblasts, adipocytes and chondrocytes (Dennis and Charbord, 2002), evidence has emerged that suggests the existence of different MSC subsets during development and possibly in adults with distinct origins and functions. Dental MSCs are generated from a unique neural crest or glial source in development (Miletich and Sharpe, 2004; Kaukua et al., 2014); most recently, Nestin⁺ BMMSCs have also been revealed as descendants of the neural crest, and unlike mesoderm-derived MSCs, they maintain hematopoietic stem cells (HSCs) but do not contribute to fetal osteochondrogenesis (Isern et al., 2014). Therefore, as an HSC niche component, MSCs have been detected in major hematopoietic sites during mouse development, such as the aorta-gonad-mesonephros and fetal liver during mid-gestation and in neonatal and adult BM (Mendes et al., 2005). However, the developmental hematopoietic function of MSCs seems to depend on their bone-forming capacity in the BM, where Osx-deficient MSCs fail to form osteoblasts in the metaphyseal area with reduced HSC function (Coşkun et al., 2014). Despite these findings, whether fetal MSCs function differently than postnatal MSCs remain unclear.

The postnatal roles of MSCs in tissue homeostasis is clearly understood. In this regard, BMMSCs have been intensively investigated for their putative contribution to skeletal remodeling (Chan et al., 2015; Worthley et al., 2015) and hematopoiesis (Derecka et al., 2020; Borella et al., 2021; Cai et al., 2022; Schloss et al., 2022). For instance, leptin receptor (Lepr)⁺ (Yue et al., 2016; Schloss et al., 2022) and Gremlin1⁺ (Worthley et al., 2015) cells are enriched for osteogenesis with either adipogenesis or chondrogenesis of perivascular BMMSCs in the adult skeletal system, and Nestin⁺ (Burt et al., 2019; Nobre et al., 2021) and platelet-derived growth factor receptor alpha (PDGFRα)⁺CD51⁺ (Lawal et al., 2017; Rux et al., 2017; Mennan et al., 2019) cells have shown co-segregation between colony-forming activity and HSC maintenance activity of BMMSCs. Moreover, dental MSCs have been shown to actively participate in the dynamic turnover of craniofacial bone (Zhao et al., 2015) and dental tissues, as represented by Gli1⁺ MSC subsets. However, critical questions remain as to whether different MSC markers overlap with each other and how distinct MSC subsets coordinate tissue homeostasis and diseases.

Although specific markers with related physiological function of MSCs in vivo remain to be elucidated, their pathophysiological contributions to diseases, as shown by declined or altered behaviors in situ and ex vivo, have been recognized in skeletal and dental systems. Osteoporosis, the skeletal degenerative disease, is characterized by loss of bone mass with increased marrow adiposity. It has been well documented that BMMSCs suffer from reduced proliferation with a differentiation shift from osteogenesis to adipogenesis in osteopenias of diverse pathologies (Liu et al., 2016; Sui et al., 2016a; Li et al., 2017). These functional impairments of BMMSCs could be attributed to the detrimental effects of diseased microenvironmental factors, such as estrogen deficiency and inflammation status (Chen et al., 2015; Shao et al., 2015). Similar damages to local resident MSCs have also been observed in other inflammatory conditions, e.g. osteoarthritis (Zhen et al., 2013) and periodontitis (Xue et al., 2016). Besides, ablation of Gli1+ cells leads to craniosynostosis and arrest of skull growth, indicating MSCs are indeed indispensible for skeletal homeostasis (Zhao et al., 2015). In addition, MSC aberrations have been revealed as a key pathogenesis in mutant-HSC-driven leukemia, in which BMMSCs could be impaired by neuropathy of the marrow niche to alter their HSC-maintaining secretome (Dong et al., 2016). The above findings further confirm the pathophysiological importance of MSC interactions with microenvironments in tissue homeostasis and diseases.

The functional characteristics of MSCs indicate their therapeutic potential. In support of this, research on MSC therapy has experienced unprecedented advances in recent years, becoming the focus of extensive work worldwide to develop approaches for a variety of diseases. In particular, evidence for the potent efficacy of MSC therapy comes from in-depth understanding of the restoration and mechanisms of systemically delivered MSCs in recipient tissue, microenvironmental homeostasis, and endogenous stem cell function. Interestingly, the benefits of MSCs are wide-ranging and remain detectable long after the disappearance of transplanted MSCs (Liu S. et al., 2015; Ng et al., 2015). Accordingly, the current recognition of MSC therapy has advanced from cell-autonomous functional determination to the essence of cell-host interplay ( Figure 2 ).

The landscape of current MSC therapy contains at least two aspects: systemic and locoregional delivery of exogenous MSCs. Among these two application strategies, systemic MSC cytotherapy, primarily through intravenous and intraperitoneal injections, is currently a research hotspot in stem cell therapy, which has been recognized to have therapeutic effects in various diseases. In particular, the immunomodulatory capability of MSCs has made them attractive and potent candidates for autoimmune and inflammatory conditions, in which they can modify the systemic microenvironment further toward a beneficial environment for tissue repair (Shi et al., 2018; Medhat et al., 2019; Borella et al., 2021; Markov et al., 2021). Their ability to suppress immune responses has become the basis for numerous preclinical and clinical studies on a range of systemic conditions and their complications, including systemic lupus erythematosus (SLE), graft versus host disease (GvHD), rheumatoid arthritis (RA) (Liu R. et al., 2015; Gu and Shi, 2016), systemic sclerosis (SSc), inflammatory bowel disease (IBD), type 1 and type 2 diabetes (T1D and T2D), osteoporosis, and osteonecrosis. Furthermore, systemically delivered MSCs benefit locoregional lesions in diverse tissues, such as myocardial infarction (Luo et al., 2017), liver fibrosis, (Watanabe et al., 2019; Shi M. et al., 2021) and renal failure (Yun and Lee, 2019). The promise of MSC cytotherapy in restoring organismal homeostasis has ushered in hundreds of clinical trials that have employed systemic infusion of MSCs.

Locoregional application, has been extensively investigated in regenerative medicine. Studies based on tissue engineering techniques have successfully regenerated/repaired craniofacial (Yu et al., 2021) and long bone defects (Zhao et al., 2021), cartilage (Kangari et al., 2020), functional tooth roots and dental pulp (Xuan et al., 2018; Guo et al., 2021), periodontal structures (Sui et al., 2019), cutaneous wounds (An et al., 2015), infarcted myocardium, neurons and nerves. Furthermore, applications are in continuous progress by optimizing MSC viability with the cell-sheet/cell-aggregate technique (Xuan et al., 2018), improving scaffold materials with nanotechnology (Kuang et al., 2016) or microencapsulation (Moshaverinia et al., 2015), and combining favorable agents for MSC function with preconditioning (Shuai et al., 2016) or co-delivery systems (Moshaverinia et al., 2015). However, a significant challenge in this field is to maintain the viability of implanted MSCs in diseased microenvironments and to maximize their efficacy during the survival period. It has been reported that recipient immune systems, primarily T cells and secreted TNF-α and IFN-γ, remarkably inhibit MSC-mediated tissue regeneration by inducing MSC apoptosis and impairing MSC differentiation (López-García and Castro-Manrreza, 2021; Xie et al., 2021) ( Figure 2 ). Further diminishing the regenerative potential, the detrimental impacts of donor comorbidities regarding aging, inflammation, and hyperglycemia are just beginning to emerge, constituting the main barrier for the application of autologous MSCs. Therefore, further studies are required toward optimizing locoregional application of MSCs, compared to systemic MSC therapy, which demonstrates distinctive advantages of minimum injuries and stable, long-lasting, and wide-ranging beneficial effects.

The promise of stem cell therapy in regenerating damaged tissues and restoring organismal homeostasis in aging and diseases has prompted thousands of clinical trials including > 700 that employ MSCs. This relies on critical molecular mechanisms. Moreover, in the future, specific interaction mechanisms will be based on the paracrine mode of action, and the study of the effects of EVs will become a hot topic in this field.

MSC therapy is a hot topic based on its current translational application and MSCs have recently been listed as promising drugs for the treatment of COVID-19, thus demonstrating their important role in the treatment of inflammatory and immune diseases. However, the feasibility and safety of MSCs have only been tested, and there is a lack of sufficient evidence on their therapeutic efficacy, particularly with regard to the lack of clear evidence to fully characterize their potential therapeutic sequelae. Although some MSCs have been shown to be safe and effective for clinical use, it is uncertain whether this can be extended to other tissues. Their therapeutic risks are mainly focused on their heterogeneity and on the initiation and promotion of tumor production; however exosomes have been shown to circumvent these concerns and are safer to use in clinical regeneration. In conclusion, extensive study is still required before MSCs can be used in a manner and extended to wider clinical applications.

PL designed, drafted and revised the manuscript. YA, TZ critically contributed to the design of the paper for important intellectual content. ST, XH, SL and FF substantially contributed to the conception of the study. JC, KX conceived and supervised the study and revised the paper. All authors contributed to the article and approved the submitted version.