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Abstract

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease associated with impaired organ functions that can seriously affect the daily life of patients. Recent SLE therapies frequently elicit adverse reactions and side effects in patients, and clinical heterogeneity is considerable. Mesenchymal stromal cells (MSCs) have anti-inflammatory, tissue repair, and immunomodulatory properties. Their ability to treat autoimmune diseases largely depends on secreted extracellular vesicles, especially exosomes. The effects of exosomes and microRNAs (miRNAs) on SLE have recently attracted interest. This review summarizes the applications of MSCs derived from bone marrow, adipocyte tissue, umbilical cord, synovial membrane, and gingival tissue, as well as exosomes to treating SLE and the key roles of miRNAs. The efficacy of MSCs infusion in SLE patients with impaired autologous MSCs are reviewed, and the potential of exosomes and their contents as drug delivery vectors for treating SLE and other autoimmune diseases in the future are briefly described.

Keywords

exosome mesenchymal stromal cell microRNA lupus

Introduction

Systemic lupus erythematosus (SLE) is a chronic, systemic inflammatory disease that affects the urinary, motor, circulatory, respiratory, digestive, and nervous systems (Fig. 1). It develops in various populations, especially in women of childbearing age and is particularly prevalent among Africans¹. It is generally characterized by alternating periods of remission and relapse, with little progressive deterioration². The cellular and molecular mechanisms involved in the pathogenesis of SLE are highly complex and are probably affected by intricate interactions among genetic, environmental, and hormonal factors³.

Figure 1.

Main clinical manifestations of systemic lupus erythematosus. Systemic lupus erythematosus is a chronic, systemic inflammatory disease that affects the urinary system, motor system, circulatory system, respiratory system, digestive system, and nervous system. Different patients are often affected by different systems and, so the clinical manifestations are also different. Clinically, skin and mucosal injuries (e.g., lupus malar rash, oral ulcer, photosensitivity, alopecia, maculopapular rash, etc.) and lupus nephritis are most common, but arthritis and serositis may also occur, and the condition is critical when neuropsychiatric manifestation is present. The clinical heterogeneity of the disease highlights the important influence of genetic factors, autoimmunity, and external environment on the disease development model, and brings challenges to the diagnosis and treatment.

A complete cure and universally effective treatment for SLE are not available. Most therapeutic schedules are designed to control and reduce disease activity. Therapeutic pharmaceuticals used to relieve lupus symptoms include non-steroidal anti-inflammatory, antimalarial, immunosuppressant drugs, and glucocorticoids⁴. However, these drugs carry a high risk of serious adverse reactions. In particular, long-term medication with glucocorticoids is often associated with serious adverse events involving the endocrine, musculoskeletal, hematopoietic, and cardiovascular systems. Osteonecrosis of the femoral head is a common and serious complication of glucocorticoids⁵.

Considering the severity of the disease, other feasible treatments for SLE have been investigated. Extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs)⁶, exosomes and their micro (mi) RNAs might serve as cell-free approaches to treating SLE. Here, we review the application of potential of exosomes derived from MSCs and miRNAs to treating SLE.

Mesenchymal Stromal Cells

Mesenchymal stromal cells are a subset of non-hematopoietic adult stromal cells⁷ with remarkable proliferative ability and potential for multiple differentiation, as well as repair, anti-inflammatory, and immunomodulatory properties (Fig. 2). Techniques for isolating and culturing MSCs from tissues, including bone marrow, adipose tissue, synovium, umbilical cord (UC), and gingiva, are gradually being refined.

Figure 2.

General characteristics of mesenchymal stromal cells. Mesenchymal stromal cells can be isolated from a variety of organs and tissues such as bone marrow, adipose tissue, umbilical cord, synovial membrane and gingiva. In addition to their good proliferative capacity and typical tri-lineage differentiation (osteogenic, chondrogenic, and lipogenic differentiation) potential, the potential for differentiation to other cells such as neurocyte, endothelial, cardiocyte, and hepatocyte, which are essential for their tissue repair function, is gradually being explored. In addition, MSCs have received extensive attention for their anti-inflammatory and immunomodulatory roles (both acquired and innate immunity) through secretion of cytokines and extracellular vesicles.

Anti-Inflammatory and Restorative Functions of MSCs

Mesenchymal stromal cells exert anti-inflammatory effects by alleviating inflammation and reducing cytokine production⁸. Exosomes from bone marrow–derived MSCs (BMMSCs) express miR-146a-5p, which inhibits the expression of interleukin-1 receptor-associated kinase 1 (IRAK1)⁹, regulates the Th17/Treg cell imbalance, and reduces pro-inflammatory cytokine production. Furthermore, MSCs eliminate the inflammatory effects of neutrophils, inhibit the formation of neutrophil extracellular traps (NETs), and reduce thrombosis, inflammation, and fibrosis induced by NETs¹⁰. Mesenchymal stromal cells can migrate and aggregate to sites of inflammation and promote injury repair. For example, allogeneic MSCs can migrate to an injured kidney after infusion. In addition to their immunomodulatory role and suppressing the autoimmune response, MSCs can be differentiated into mesangial cells to treat lupus nephritis (LN)¹¹.

Immunoregulatory Properties of MSCs

Mesenchymal stromal cells exert unique immunosuppressive effects in innate and adaptive immunity by inhibiting the proliferation and activities of immune cells such as macrophages, dendritic cells (DCs), natural killer (NK) cells, B lymphocytes, and T lymphocytes¹¹.

Mesenchymal stromal cells derived from human gingiva (GMSCs) reduce the infiltration of CD8⁺ T, Th1, Th17, and other pro-inflammatory cells, and increase the proportion of immunosuppressive cells such as regulatory T (Treg) cells¹². Mesenchymal stromal cells interfere with B cell proliferation and migration, as well as antibody and cytokine production¹. They can also indirectly inhibit B cell function by inhibiting T cells¹³. Macrophages can take on two main phenotypes: inflammatory M1 and anti-inflammatory M2 macrophages. Most MSCs injected intravenously into mouse models of asthma travel through the bloodstream and eventually reach the lungs, where they die and are phagocytosed by macrophages. Such macrophages can differentiate into the immunosuppressive M2 phenotype and decrease the M1/M2 ratio in vivo, which is one mechanism through which MSCs play a regulatory role¹⁴.

Extracellular Vesicles Released From MSCs

In addition to classical soluble factors such as cytokines that play a role in paracrine signaling, the role of EVs released from MSCs (MSC-EVs) in intercellular communication should not be ignored¹⁵. Extracellular vesicles are a class of cell-derived heterogeneous membrane structures that can be apoptotic bodies, microvesicles, microparticles, or exosomes¹⁶. The immunosuppressive effects of MSCs are mainly manifested through their EVs¹⁷. Exosomes are rich in proteins, transcription factors, lipids, DNA, miRNAs, mRNAs, and cytokines. They act on target cells by binding to receptors in target tissues or by fusion with plasma membranes¹⁸.

Diagnostic Value of Exosomes and Their miRNAs

Exosomes are involved in cell migration, the immune response, cell differentiation, antigen presentation, and tumor invasion, among which miRNAs play important roles^19,20. Non-coding miRNAs can regulate pathways associated with gene expression by interacting with specific targets after their extracellular transport by EVs²¹. Micro RNA entry into exosomes is not random and is mediated by unique miRNA sorting mechanisms²², such as the Endosomal Sorting Complex Required for Transport (ESCRT)²³. Exosomes and their miRNAs have potential as diagnostic and therapeutic agents in autoimmune diseases²⁴. For example, primary fibrosis in LN is closely associated with exosomal miR-129 isolated from urine, suggesting a predictive role of miR-129 in disease progression²⁴. The expression of miR-21 and let-7A in urinary exosomes is obviously downregulated in patients with active LN compared with those who have inactive LN, but this rebounds during remission, suggesting that they could serve as biomarkers of active LN activity²⁵. Using MSC-EVs to deliver miRNAs to specific cells is a potential mechanism of alleviating tissue damage²⁶. Elevating the expression of programmed cell death ligand 1 via gene transfection in EVs of MSCs enhances their immunosuppressive ability²⁷. This indicated that enhancing EV function has potential clinical applications.

Advances in exosomes and their miRNAs as biomarkers have suggested their potential therapeutic value. Exosome-based therapies avoid the need to administer live cells⁶. Therefore, exosome-based therapies might be suitable alternatives to conventional cell therapy for SLE. Exosomes derived from antigen-presenting cells such as DCs and MSCs are currently regarded as potential cell-free approaches to treating autoimmune diseases²⁸.

MSCs in SLE Treatment

Allogenic MSC Transplantation in SLE

Bone marrow, adipose tissues, gingival tissues, UCs, and the synovium are sources of allogenic MSCs that can be used to treat SLE.

Bone marrow–derived MSCs and exosomes

For 40 years since their initial description, BMMSCs have become the most widely studied MSC population and are considered the gold standard for clinical MSC application²⁹. The production of autoantibodies in patients with SLE depends on the activation of T-cell-assisted B cells. Therefore, regulating the activity of upstream T cells might restrict excessive B-cell activity in SLE¹³. Clinically, the immunological regulation of MSCs is applicable not only as therapy for SLE but also for connective tissue diseases (CTDs), graft-versus-host disease (GVHD), and other immune disorders. For example, a clinical trial found that BMMSCs relieved symptoms in 25 patients with GVHD without significant adverse events³⁰.

Not only do BMMSCs inhibit the differentiation of T cells into T follicular helper (Tfh) cells, they also inhibit differentiated Tfh cell proliferation and interleukin (IL)-21 production, thus alleviating LN in mice³¹. Human BMMSCs inhibit T-cell-mediated B-cell proliferation, plasma cell differentiation, and antibody production in vitro¹³. In addition, MSCs secrete exosomes containing miRNAs that inhibit cytokine secretion in macrophages by regulating Toll-like receptor (TLR)-related signaling pathways³². Transfer RNA–derived small RNA (tsRNA)-21109 in BMMSC exosomes inhibits macrophage polarization toward the M1 phenotype in vitro, thus contributing to the development of a new specific therapeutic target for SLE³³. Allogeneic BMMSC transplantation also enhances the function of autologous BMMSCs and improves osteopenia in a mouse model of lupus³⁴.

However, bone marrow might not be the optimal source of MSCs. In addition to an invasive and painful isolation procedure, MSCs are scant in bone marrow aspirates, and their qualitative and quantitative properties are affected by donor age³⁵.

Adipose tissue–derived MSCs and exosomes

Differentiation potential, proteomic characteristics, gene expression, and immunological characteristics differ between adipose tissue–derived MSCs (ADSCs) and BMMSCs. Adipose tissue–derived MSCs are easier to isolate and clinically safer to collect than BMMSCs³⁶. Furthermore, ADSCs more effectively inhibit peripheral blood T cells, are more regenerative, and have more adaptable electrokinetic properties than BMMSCs³⁷. Combining ADSCs with exosomes is more effective than injecting them alone and could be considered as a future stromal cell treatment option^38,39. The results of treating a patient with SLE in Canada using autologous ADSCs were significant and stable⁴⁰. A clinical trial in Iran found that ADSC transplantation is effective against LN, whereas a single dose might be insufficient to maintain remission⁴¹.

Adipose tissue–derived MSCs inhibit the initial differentiation of T cells into Th17 cells and reduce IL-17 secretion by regulating the protein kinase B/mammalian target of rapamycin complex 1/Ribosomal protein S6 kinase beta-1/Hypoxia-inducible factor 1-alpha/Th17 (AKT/mTORC1/p70S6K/HIF-1A)/Th17 signaling pathway in MLR/lpr mice⁴². Adipose tissue–derived MSCs also induce the differentiation of macrophages into the M2 phenotype via the exosomal-mediated transfection of active signal transducer and activator of transcription 3 (STAT3)⁴³. Controlled clinical trials of autologous ADSCs for osteoarthritis found that intra-articular injections of ADSCs improved joint function and pain relief in patients⁴⁴. Exosomes of ADSCs in patients with osteoarthritis are rich in miR-145 and miR-221, which can downregulate pro-inflammatory factor expression in periosteum cells in vitro⁴⁵.

The properties of ADSCs can be enhanced in several ways. For example, incubating them with glial cell-derived neurotrophic factor promotes their migration and differentiation⁴⁶. Conditioning ADSCs with interferon-gamma (IFN-γ) improves their immunosuppressive potential in conditioned media and EVs⁴⁷.

Umbilical cord–derived MSCs and exosomes

Umbilical cords might be an ideal substitute for ADSCs and BMMSCs, as they are discarded after birth and thus can be easily collected. The amplification rate is higher in vitro for umbilical cord–derived mesenchymal stromal cells (UC-MSCs) than BMMSCs⁴⁸. More importantly, UC-MSCs have similar or superior immunomodulatory characteristics to MSCs derived from other sources^48,49.

Clinical trials have revealed that UC-MSCs are significantly effective for treating SLE (Table 1). In fact, MSC therapy can reduce abnormal apoptotic cell accumulation in SLE through phagocytosis, resulting in the promotion of prostaglandin E2 (PGE2)-mediated immunosuppression⁵⁰. Moreover, MSCs promote CD1c⁺ DC upregulation in peripheral blood and FLT3L in serum, inhibiting the inflammatory response to lupus⁵¹. Furthermore, UC-MSCs can prevent SLE by synthesizing transforming growth factor (TGF)-β1 that promotes the production of IL-10⁺ B regulatory cells (Bregs) and correct the Treg/Th17/Th1 imbalance in mice⁵².

Table 1.

Clinical Trial and Application of MSCs in Systemic Lupus Erythematosus.

MSCs	Disease	Patients	Administration	Outcome	Adverse events	Year
BMMSCs (Autologous)	SLE⁵³	2	1 × 10⁶/kg; intravenous infusion	CD4+CD25+FoxP3+ cells increased but the disease did not exhibit remission.	Not found.	2010
ADMSCs (Autologous)	SLE⁴⁰	1	Intranasal injection (1 × 10⁸), lymph node injection (1 × 10⁸), intravenous transfusions (379 × 10⁶, 234 × 10⁶).	The result was good, and the subsequent physical condition remained stable.	There were only mild adverse reactions and spontaneous recovery.	2021
UC-MSCs	SLE⁵¹	21	1 × 10⁷/kg; intravenous infusion	CD1c+ dendritic cells and the cytokine FMS-related Tyrosine kinase 3-ligand increased. Most patients experience varying degrees of remission.	Not found.	2019
UC-MSCs	Lupus nephritis⁵⁴	12	2 × 10⁸; intravenous infusion	The trial was stopped when it did not show the expected efficacy.	Subcutaneous abscess, leucopenia, and pneumonia.	2017
BMMSCs	SLE-IV active proliferative nephritis⁵⁵	3	9 × 10⁸; intravenous infusion	Proteinuria levels improved. SLE disease activity index was improved. Symptoms are relieved to varying degrees.	Not found.	2018
UC-MSCs BMMSCs	Persistently active SLE⁵⁶	87	1 × 10⁶/kg; intravenous infusion	Disease activity declined. Symptoms were relieved and organ dysfunction improved.	Not found.	2013
ADMSCs	Refractory lupus nephritis⁴¹	9	2 × 10⁶/kg; intravenous infusion	Urinary protein levels and disease activity decreased. A single dose may not provide long-term relief.	Not found.	2021
UC-MSCs	Lupus nephritis⁵⁷	20	3 × 10⁷/kg intravenous infusion	The disease improved significantly and the recurrence rate was low.	Not found.	2014

ADSCs: adipose tissue–derived stem cells; BMMSCs: bone marrow–derived mesenchymal stromal cells; IL: interleukin; MSC: mesenchymal stromal cell; SLE: systemic lupus erythematosus; UC-MSC: umbilical cord–derived mesenchymal stromal cell.

Overactivated complement C5a and C5B-9 might be involved in the progression of LN, and UC-MSCs can improve LN in mice by secreting factor H to inhibit C5 activation⁵⁸. Current investigations into human UC-MSCs (hUC-MSCs) mainly focus on the application of exosomes. For example, hUC-MSCs induce T-cell senescence and ameliorate lupus by regulating sirtuin 1 (SIRT1)/tumor protein P53 (p53) signaling in CD4⁺ T cells via miR-199a-5p transfer⁵⁹. Human UC-MSCs can also release exosomes to induce the anti-inflammatory polarization of macrophages and improve SLE-associated diffuse alveolar hemorrhage in mice⁶⁰. Exosomes released by UC-MSCs significantly inhibit the production of pro-inflammatory cytokines such as IFN-γ, IL-2, and TNF-α and increase the production of anti-inflammatory cytokines such as IL-10⁶¹.

Several clinical trials have confirmed the safety and effectiveness of UC-MSCs in patients with SLE. However, repeated injections of MSCs are necessary to avoid disease recurrence⁶².

Gingival MSCs and exosomes

A population of human gingival stromal cells (GMSCs) has self-renewal and multipotent differentiation capabilities⁶³. Furthermore, GMSCs have better stem cell properties and immune characteristics than BMMSCs⁶⁴, are not dependent on growth factor and serum supplements, are non-tumorigenic, and have phenotypic stability and high telomerase activity in long-term culture in vitro⁶⁵. The phenotype and immunoregulatory functions of GMSCs isolated from patients with active SLE and healthy controls might be similar⁶⁵. However, clinical trials of GMSCs for treating SLE have not substantially progressed.

Gingival MSCs exert preventive and therapeutic effects on lupus, and their exosomes promote M2 polarization of macrophages^66,67. Gingival MSCs convert ADP or ATP to adenosine via elevated CD39 and CD73⁶⁸ expression. They also promote transformation from an ATP-driven pro-inflammatory to an adenosine-driven anti-inflammatory environment, thus regulating naive CD4⁺ T-cell differentiation⁶⁸. Furthermore, GMSCs limit the development of proteinuria as well as autoantibodies, and decrease the frequency of plasma cells and severity of LN by directly inhibiting B-cell activation, proliferation, and differentiation⁶⁹. Abnormal activation of the mTOR signaling pathway plays a central role in cell aging and GMSC-EVs can significantly inhibit mTOR/PS6 signaling; thus, GMSC-EVs might help to alleviate abnormal cell senescence in lupus tissues⁷⁰.

Synovium-derived MSCs (SMSCs) and exosomes

Arthritis is a generally non-invasive, common clinical manifestation of SLE. Advances in imaging technology have clarified that chronic synovitis is more prevalent than was previously estimated⁷¹. Immune cells, especially T cells, play a critical role in the pathogenesis of lupus arthritis⁷². Synovium-derived MSCs have powerful immunomodulatory activities⁷³, such as the inhibition of T-cell proliferation. Human synovium–derived mesenchymal stromal cell (hSMSCs) co-cultured with T cells inhibit their proliferation while having high proliferative capacity and limited senescence⁷⁴. Intra-articular hSMSC injections restore the Th17/Treg and Th1/Th2 cell balance in animal models of rheumatoid arthritis⁷⁵. Therefore, SMSCs might have similar therapeutic potential against SLE arthritis. However, the effects of SMSCs on NK, antigen-presenting, and B cells await exploration.

Exosomes of hSMSCs have abundant miR-129-5p, which significantly reduces cartilage cell inflammation and apoptosis. Human SMSCs injected into patients with osteoarthritis results in miR-129-5p in exosomes specifically targeting high mobility group box 1 (HMGB1) and attenuating the HMGB1-mediated inflammatory response⁷⁶.

The pathogenesis of lupus also involves upregulated HMGB1⁷⁷; therefore, HMGB1 might be a potential target for treating SLE. Lupus is often treated using glucocorticoids, but prolonged exposure can lead to necrosis of the femoral head. Infused SMSCs prevent glucocorticoid-induced femoral head necrosis in rats by promoting bone tissue maintenance and regeneration via exosome secretion⁷⁸. In addition, the extracellular matrix associated with SMSCs enhances anti-inflammatory properties and the proliferative potential of articular cartilage via the SIRT1 pathway⁷⁹. Therefore, SMSCs are more suitable for treating joint lesions than other sources of MSCs.

Currently, MSCs derived from various sources have shown immunomodulatory effects in animal models, and allogeneic MSCs have exerted substantial clinical effects in SLE treatment. However, the mechanism through which MSCs alleviate SLE remains unclear. Mesenchymal stem cells have immune-regulatory, anti-inflammatory, and tissue repair functions. Specific MSCs might exert superior effects on individual systemic symptoms of SLE, like those of SMSCs in arthritis. Therefore, the feasibility and safety of sampling MSCs must be determined to obtain ethical approval before their clinical application can be promoted. Moreover, the effects and potential side effects of MSCs obtained from various sources should be compared. Like MSCs, exosomes derived from them might be a potential therapeutic approach.

Autologous MSC Transplantation in SLE

Application of autologous MSCs

Therapy is more suitable with autologous cells to prevent immune reactions to allogeneic cells in humans⁸⁰. Although autologous MSCs to treat SLE does not elicit side effects and increased CD4⁺CD25⁺Foxp3⁺ Treg cells, disease activity is not affected, and later stages of the disease were not prevented⁵³. Lupus MSCs are ineffective against SLE mice, and autologous MSCs are ineffective in treating human SLE⁸⁰. Thus, autologous MSCs might not produce desirable effects in patients with SLA⁸⁰.

MSC dysfunction in patients with SLE

Mesenchymal stem cells from patients with SLE have abnormal proliferation, immune regulation, and phenotypes⁸¹, as well as an altered intracellular constitution, especially pertaining to miRNA expression.

MicroRNA signaling in BMMSCs from patients with SLE is unique; abnormal miR-663 elevation might be associated with disease activity. Specifically, miR-663 targets TGF-β1 and inhibits BMMSC proliferation and migration, thus inhibiting any decrease in the proportion of Tfh cells or increase in the proportion of Treg cells normally mediated by BMMSCs⁸². Intracellular miR-153-3p overexpression reduces UC-MSC proliferation and migration, inhibits the UC-MSC-mediated decrease in the population of Tfh cells, and increases that of Tregs by inhibiting PELI1⁸³. The onset of lupus is associated with a triggered Treg/Th17 imbalance in BMMSCs due to decreased Let-7f expression⁸⁴. Furthermore, MSCs in patients with SLE have abnormal differentiation and senescence phenotypes, a senescent morphology, and increased proportions (%) of apoptotic cells. The proliferation potential of MSCs is limited in vitro, and gene expression associated with the senescence secretion phenotype is significantly increased⁸⁵.

Gingival MSCs isolated from patients with active SLE have phenotypes and persistent immunomodulatory functions like those of healthy controls⁶⁵. The application of autologous MSCs to SLE requires further investigation.

Conditioned MSCs

Because autologous cell therapy can prevent allogeneic reactions in humans⁸⁰, effort has been directed to repair autologous MSCs using manipulations in vivo and ex vivo (Table 2).

Table 2.

Effects of Pre-Treated MSCs Combined With Other Cell Types and Drugs.

Pre-treatment	Type	Response	Specific effect	Year
Rapamycin⁸⁶	BMMSCs	Improved	Reverse aging phenotype of Lupus BMMSCs Improved immune regulation and increased the proportion of Treg/Th17 cells	2016
Ethyl pyruvate⁸⁷	BMMSCs	Improved	Reverse aging phenotype of BMMSCs Improved immune regulation of Treg	2019
Acetylsalicylic acid⁸⁸	Inflamed GMSCs	Improved	Restore the immunomodulatory properties of impaired inflamed GMSCs. Improve T cell apoptosis mediated by IGMSCs	2019
HCQ⁸⁹	hUC-MSCs	Improved	Enhance MSCs to improve renal morphology and function	2018
GDNF⁴⁶	ADSCs	Improved	Protective effect of GDNF modified ADSC on renal interstitial fibrosis was enhanced.	2021
Phorbol ester⁹⁰	BMMSCs	Improved	Activate mesenchymal stem cells to regulate B cells and improve lupus symptoms	2020
Metformin⁹¹	ADSCs	Improved	Metformin enhanced STAT1 expression of ADSCs and enhanced its immunomodulatory effect	2020
Combination therapy	Type	Response	Specific effect	Year
Hematopoietic stem cells⁹²	Amnion-derived MSCs	Improved	Transfusion-related graft-versus-host reaction is rare. Improve kidney function	2021
CsA⁹³	ADSCs	Improved	Reduce immunosuppressant dosage while maintaining or improving therapeutic effect	2017
Rapamycin⁹³	ADSCs	Improved	Promotes the function of anti-inflammatory Treg lymphocytes.	2017
MMF⁹³	ADSCs	Improved	Synergistic effect	2017
Glucocorticoids⁹³	ADSCs	Improved	Induced upregulation of Th17-related responses	2017
HCQ⁸⁹	hUC-MSCs	Ineffective	Less effective than HCQ and MSCs alone in mice	2018
IL-37⁹⁴	BMMSCs	Improved	To systemic lupus erythematosus additive therapeutic effect	2020

ADSCs: adipose tissue–derived stem cells; BMMSCs: bone marrow–derived mesenchymal stromal cells; GDNF: glial cell line–derived neurotrophic factor; GMSCs: gingiva-derived mesenchymal stromal cells; HCQ: hydroxychloroquine; HSC: haematopoietic stem cell; MMF: mycophenolate mofetil; IGMSCs: inflammatory gingiva-derived mesenchymal stromal cells; MSC: mesenchymal stromal cell; hUC-MSC: human umbilical cord–derived mesenchymal stromal cell.

Altering aging-related genes or signaling pathways can partially or completely reverse the aging phenotype and the defective immunoregulatory features of MSCs in patients with SLE⁹⁵. Therefore, reversing MSC senescence might improve its therapeutic effects on SLE⁸¹.

The activated mTOR pathway is involved in MSC senescence in patients with SLE. Treating autologous MSCs derived from patients with SLE with the mTOR signaling inhibitor rapamycin (RAPA) ex vivo then infusing them might improve the immune-regulation ability of BMMSCs. Notably, RAPA increases the proportion of Treg/Th17 cells and regulates the secretion of related cytokines⁸⁶. In addition, treating BMMSCs with ethyl pyruvate reverses BMMSC aging by blocking the HMGB1/TLR4/NF-κB signaling pathway, thus improving Treg-cell-related immune regulation⁸⁷. Let-7f-5p can somewhat reduce the inflammatory response of SLE-BMMSCs by targeting NOD-like receptor protein 3 (NLRP3)⁹⁶. Other MSC pre-conditioning methods might be applied to restore the functions of autoimmune MSCs. Such modulators might increase the possibility of applying autoimmune MSCs to autoimmune diseases. For example, incubating inflammatory GMSCs (IGMSCs) that have impaired immune-regulation ability with acetylsalicylic acid upregulates Fas ligand expression, thus enhancing the apoptosis of T cells mediated by IGMSC⁸⁸.

Development of Combination Therapy

Among the drugs that are currently prescribed to treat SLE, immunosuppressants are often limited due to the risk of side effects. A combination of MSCs and immunosuppressants has shown promise for patients with refractory SLE. Combination therapies decrease the amount of immunosuppressants required to reduce immune activity in SLE⁹³.

Mesenchymal stromal cells exert synergistic effects on immunosuppressants such as the calcineurin inhibitor CsA, the mTOR inhibitor RAPA, mycophenolate mofetil (MMF), dexamethasone (Dex), and prednisone. The combination of MSCs and immunosuppressants significantly alters the activation and balance of T-lymphocyte subsets and reverses the adverse effects of immunosuppressants such as the prednisone-, Dex-, or MMF-induced increase in T-cell differentiation into Th17 cells. However, MSC activity and function have not been significantly inhibited⁹³. The results of combinations of immunosuppressants on MSCs differ based on the included drugs. For example, a combination of tacrolimus and RAPA antagonizes, whereas Dex does not alter the immunosuppressive effects of transplanted MSCs⁹³.

In conclusion, although combining drugs with MSC transplantation is a promising new therapeutic strategy, further studies are warranted to ensure their effectiveness and safety (Table 2).

Prospects and Challenges of Cell-Free Therapy

Although live MSCs have gradually been applied in clinical practice as therapy, dangers include degrees of immune rejection, low cell survival rates, senescence, and carcinogenic potential⁹⁷. Adequate funding and technology are also required to prepare and preserve live cells, which limits the widespread application of MSCs as therapy in hospital environments. However, the therapeutic effects of MSC-derived EVs, especially exosomes, are similar to those of MSCs. Being cell-free, exosomes have more advantages than MSCs, are easier to preserve and manage, have no immunogenicity, and can easily cross the blood–brain barrier⁹⁸, which is considered a promising new treatment option. However, many aspects still require optimization before large quantities of such exosomes can serve as human therapies¹⁷.

The first issue is the high cost and low efficiency of current methods of extracting exosomes from cells, and related processes have not been standardized⁹⁹. Differential ultracentrifugation can generate the purest exosomes, but it is time-consuming¹⁰⁰. Artificial exosomes might guarantee production and facilitate widespread commercialization. Attempts are ongoing to increase EV production by modifying culture conditions and conducting specific interventions for MSCs¹⁰¹. Another issue is the efficiency of exosome homing to specific lesion sites. Extracellular vesicles such as exosomes can be homed to a portion of injured tissue dependent on the expression of CD44, CD29, or CD73¹⁰². However, most intravenously injected exosomes accumulate at sites where the mononuclear phagocyte system (MPS) is active¹⁰³. Artificial modification of exosome membranes to increase the proportions of them that reach target cells is essential to improve bioavailability¹⁷. Because the pathogenesis of lupus is different caused by different factors, conventional drugs are only effective for a certain type of patients. Most current studies of potential therapeutic mechanisms of miRNAs in MSC exosomes target a specific miRNA, which provides great support for the development of targeted therapy. However, whether transfecting several miRNAs together into exosomes or inhibiting them will increase their effectiveness or cause side effects is unknown. A single miRNA can target multiple mRNAs, so exosomes carrying specific miRNAs delivered intravenously might elicit side effects¹⁰⁴. Further studies are needed to decode the complexity of exosome components to better understand the safety of their combined effects on target tissues. Bioengineering efforts are also needed to achieve the amplification and safe production of compositionally homogeneous exosomes containing specific miRNAs or inhibitors¹⁰⁵ of miRNAs¹⁰⁶. The optimal dose and frequency of exosome administration should also be determined to maximize efficiency¹⁰⁷.

Conclusions

The anti-inflammatory repair potential, immunomodulatory, and specific immunological properties of MSCs hold promise for using allogeneic MSCs to treat SLE with abnormal autologous MSC function. Investigations into the effects of chemical and other manipulations to improve MSCs before delivery and the application of exosomes as drug delivery vectors in treating SLE are currently underway. Roles for exosomes and their miRNAs in the diagnosis and treatment of SLE have been demonstrated. Tissue engineering, biomaterials, and stem cell biology offer a brighter future for patients with SLE through the large-scale preparation of specific exosomes/miRNAs.

Footnotes

Acknowledgements

We are grateful to the Second Affiliated Hospital of Fujian Medical University for providing infrastructure facilities.

Author Contributions

YJL, ZC, and SL: concept and design of manuscript. YJL drafted and finalized the manuscript. ZC and SL drafted the manuscript. ZC, HBM, and SL revised the manuscript and provided critical advice about the content. All authors contributed to the article and approved the submitted version.

Availability of Data and Materials

Not applicable

Ethical Approval

Not applicable.

Statement of Human and Animal Rights

This article does not contain any studies with human or animal subjects.

Statement of Informed Consent

There are no human subjects in this article and informed consent is not applicable.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Science and Technology Bureau of Quanzhou (grant 2020CT003), the Natural Science Foundation of Fujian Province (grant 2020J01219), and the Science and Technology Bureau of Quanzhou (grant 2017Z009).

ORCID iD

Zhen Chen

References

Tang

Liu

Peng

Liao

Luo

Sun

Tang

Y-L

Luo

X-Q

. Functional characteristics and application of mesenchymal stem cells in systemic lupus erythematosus. Arch Immunol Ther Exp (Warsz). 2021;69(1):7.

Khan

Granville

Malkani

Chathampally

. Health-related quality of life improvements in systemic lupus erythematosus derived from a digital therapeutic plus tele-health coaching intervention: randomized controlled pilot trial. J Med Internet Res. 2020;22(10):e23868.

Ukadike

Mustelin

. Implications of endogenous retroelements in the etiopathogenesis of systemic lupus erythematosus. J Clin Med. 2021;10(4):856.

Kariburyo

Xie

Sah

Lofland

. Real-world medication use and economic outcomes in incident systemic lupus erythematosus patients in the United States. J Med Econ. 2020;23(1):1–9.

Caplan

Fett

Rosenbach

Werth

Micheletti

. Prevention and management of glucocorticoid-induced side effects: a comprehensive review: a review of glucocorticoid pharmacology and bone health. J Am Acad Dermatol. 2017; 76(1):1–9.

Eleuteri

Fierabracci

. Insights into the secretome of mesenchymal stem cells and its potential applications. Int J Mol Sci. 2019;20(18):4597.

Radmanesh

Mahmoudi

Yazdanpanah

Keyvani

Kia

Nikpoor

Zafari

Esmaeili

. The immunomodulatory effects of mesenchymal stromal cell-based therapy in human and animal models of systemic lupus erythematosus. IUBMB Life. 2020;72(11):2366–81.

Liu

Ding

Zhou

Long

Shen

Zhang

Wei

. Human umbilical cord mesenchymal stem cell conditioned medium attenuates renal fibrosis by reducing inflammation and epithelial-to-mesenchymal transition via the TLR4/NF-kappaB signaling pathway in vivo and in vitro. Stem Cell Res Ther. 2018;9(1):7.

Huang

Chen

. Bone marrow mesenchymal stem cell-derived exosomes induce the Th17/Treg imbalance in immune thrombocytopenia through miR-146a-5p/IRAK1 axis. Hum Cell. 2021;34(5):1360–74.

10.

Magana-Guerrero

Dominguez-Lopez

Martinez-Aboytes

Buentello-Volante

Garfias

. Human amniotic membrane mesenchymal stem cells inhibit neutrophil extracellular traps through TSG-6. Sci Rep. 2017;7(1):12426.

11.

Chen

Sun

. An update for mesenchymal stem cell therapy in lupus nephritis. Kidney Dis (Basel). 2021;7(2):79–89.

12.

Zhao

Chen

Huang

Wang

Zhou

Cao

Sun

Liu

Bellanti

, et al. Human gingiva tissue-derived MSC ameliorates immune-mediated bone marrow failure of aplastic anemia via suppression of Th1 and Th17 cells and enhancement of CD4+Foxp3+ regulatory T cells differentiation. Am J Transl Res. 2019;11(12):7627–43.

13.

Rosado

Bernardo

Scarsella

Conforti

Giorda

Biagini

Cascioli

Rossi

Guzzo

Vivarelli

Strologo

, et al. Inhibition of B-cell proliferation and antibody production by mesenchymal stromal cells is mediated by T cells. Stem Cells Dev. 2015;24(1):93–103.

14.

Braza

Dirou

Forest

Sauzeau

Hassoun

Chesné

Cheminant-Muller

Sagan

Magnan

Lemarchand

. Mesenchymal stem cells induce suppressive macrophages through phagocytosis in a mouse model of asthma. Stem Cells. 2016;34(7):1836–45.

15.

Dabrowska

Andrzejewska

Lukomska

Janowski

. Neuroinflammation as a target for treatment of stroke using mesenchymal stem cells and extracellular vesicles. J Neuroinflammation. 2019;16(1):178.

16.

Doyle

Wang

. Overview of extracellular vesicles, their origin, composition, purpose, and methods for exosome isolation and analysis. Cells. 2019;8(7):727.

17.

Harrell

Jovicic

Djonov

Arsenijevic

Volarevic

. Mesenchymal stem cell-derived exosomes and other extracellular vesicles as new remedies in the therapy of inflammatory diseases. Cells. 2019;8(12):1605.

18.

Seo

Kim

Hong

. Stem cell-derived extracellular vesicles as immunomodulatory therapeutics. Stem Cells Int. 2019;2019:5126156.

19.

Nabet

. Exosomes in the tumor microenvironment as mediators of cancer therapy resistance. Mol Cancer. 2019;18(1):32.

20.

Yan

Chen

Wang

Yuan

Kang

Zhang

Machens

Rinkevich

Chen

, et al. Milk exosomes-mediated miR-31-5p delivery accelerates diabetic wound healing through promoting angiogenesis. Drug Deliv. 2022;29(1):214–28.

21.

Leavitt

Limoli

Baulch

. miRNA-based therapeutic potential of stem cell-derived extracellular vesicles: a safe cell-free treatment to ameliorate radiation-induced brain injury. Int J Radiat Biol. 2019;95(4):427–35.

22.

Garcia-Martin

Wang

Brandão

Zanotto

Shah

Kumar Patel

Schilling

Kahn

. MicroRNA sequence codes for small extracellular vesicle release and cellular retention. Nature. 2022;601(7893):446–51.

23.

Juan

Fürthauer

. Biogenesis and function of ESCRT-dependent extracellular vesicles. Semin Cell Dev Biol. 2018; 74:66–77.

24.

Mirzaei

Zamani

Hajibaba

Rasouli-Saravani

Noroozbeygi

Gorgani

Hosseini-Fard

Jalalifar

Ajdarkosh

Abedi

Keyvani

, et al. The pathogenic, therapeutic and diagnostic role of exosomal microRNA in the autoimmune diseases. J Neuroimmunol. 2021;358:577640.

25.

Tangtanatakul

Klinchanhom

Sodsai

Sutichet

Promjeen

Avihingsanon

Hirankarn

. Down-regulation of let-7a and miR-21 in urine exosomes from lupus nephritis patients during disease flare. Asian Pac J Allergy Immunol. 2019;37(4):189–97.

26.

Chen

Zheng

Huang

Jin

Gong

, et al. BMSCs-derived miR-223-containing exosomes contribute to liver protection in experimental autoimmune hepatitis. Mol Immunol. 2018;93: 38–46.

27.

Fei

Dai

Fan

Shen

Zhang

Chu

Peng

Zhou

, et al. Mesenchymal stem cell-derived extracellular vesicles with high PD-L1 expression for autoimmune diseases treatment. Adv Mater. 2022;34(1):e2106265.

28.

Elashiry

Elsayed

Cutler

. Exogenous and endogenous dendritic cell-derived exosomes: lessons learned for immunotherapy and disease pathogenesis. Cells. 2021;11(1):115.

29.

Batsali

Kastrinaki

Papadaki

Pontikoglou

. Mesenchymal stem cells derived from Wharton’s Jelly of the umbilical cord: biological properties and emerging clinical applications. Curr Stem Cell Res Ther. 2013;8(2):144–155.

30.

Muroi

Miyamura

Okada

Yamashita

Murata

Ishikawa

Uike

Hidaka

Kobayashi

Imamura

Tanaka

, et al. Bone marrow-derived mesenchymal stem cells (JR-031) for steroid-refractory grade III or IV acute graft-versus-host disease: a phase II/III study. Int J Hematol. 2016;103(2):243–50.

31.

Yang

Zou

. Bone marrow-derived mesenchymal stem cells inhibit T follicular helper cell in lupus-prone mice. Lupus. 2018;27(1):49–59.

32.

Phinney

Di Giuseppe

Njah

Sala

Shiva

St Croix

Stolz

Watkins

Leikauf

Kolls

, et al. Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs. Nat Commun. 2015;6:8472.

33.

Dou

Zhang

Wang

Yan

. Mesenchymal stem cell exosomal tsRNA-21109 alleviate systemic lupus erythematosus by inhibiting macrophage M1 polarization. Mol Immunol. 2021;139:106–14.

34.

Liu

Chen

Hamamura

Moshaverinia

Yang

Liu

Jin

Shi

. MSC transplantation improves osteopenia via epigenetic regulation of notch signaling in lupus. Cell Metab. 2015;22(4):X606–18.

35.

Mueller

Glowacki

. Age-related decline in the osteogenic potential of human bone marrow cells cultured in three-dimensional collagen sponges. J Cell Biochem. 2001;82(4):583–90.

36.

Strioga

Viswanathan

Darinskas

Slaby

Michalek

. Same or not the same? Comparison of adipose tissue-derived versus bone marrow-derived mesenchymal stem and stromal cells. Stem Cells Dev. 2012;21(14):2724–52.

37.

El-Badawy

Amer

Abdelbaset

Sherif

Abo-Elela

Ghallab

Abdelhamid

Ismail

El-Badri

. Adipose stem cells display higher regenerative capacities and more adaptable electro-kinetic properties compared to bone marrow-derived mesenchymal stromal cells. Sci Rep. 2016;6:37801.

38.

Chen

Wallace

Yuen

Kao

Chen

Shao

P-L

Chen

Y-L

Chai

H-T

Lin

K-C

Liu

C-F

, et al. Intravenous administration of xenogenic adipose-derived mesenchymal stem cells (ADMSC) and ADMSC-derived exosomes markedly reduced brain infarct volume and preserved neurological function in rat after acute ischemic stroke. Oncotarget. 2016;7(46):74537–56.

39.

Lin

Yip

Shao

Chen

Yang

C-C

Sun

C-K

Kao

G-S

Chen

S-Y

Chai

H-T

, et al. Combination of adipose-derived mesenchymal stem cells (ADMSC) and ADMSC-derived exosomes for protecting kidney from acute ischemia-reperfusion injury. Int J Cardiol. 2016;216:173–85.

40.

Wong

Medrano

Hoftman

Jones

McCurdy

. Uncharted waters: mesenchymal stem cell treatment for pediatric refractory rheumatic diseases; a single center case series. Pediatr Rheumatol Online J. 2021;19(1):87.

41.

Ranjbar

Hassanzadeh

Jahandoust

Miri

Bidkhori

Monzavi

Sanjar-Moussavi

Matin

Shariati-Sarabi

. Allogeneic adipose-derived mesenchymal stromal cell transplantation for refractory lupus nephritis: results of a phase I clinical trial. Curr Res Transl Med. 2022;70(2):103324.

42.

Zhang

Gao

Liu

Han

Tian

Wei

Zhang

. Human umbilical cord mesenchymal stem cell-derived small extracellular vesicles ameliorate collagen-induced arthritis via immunomodulatory T lymphocytes. Mol Immunol. 2021;135:36–44.

43.

Zhao

Shang

Pan

Bai

Zhang

Guo

Zhang

Wang

. Exosomes from adipose-derived stem cells attenuate adipose inflammation and obesity through polarizing M2 macrophages and beiging in white adipose tissue. Diabetes. 2018;67(2):235–47.

44.

Lee

Kim

Jin

. Intra-articular injection of autologous adipose tissue-derived mesenchymal stem cells for the treatment of knee osteoarthritis: a phase IIb, randomized, placebo-controlled clinical trial. Stem Cells Transl Med. 2019;8(6):504–11.

45.

Zhao

Chen

Peng

Yuan

. Exosomes from adiposederived stem cells promote chondrogenesis and suppress inflammation by upregulating miR145 and miR221. Mol Med Rep. 2020;21(4):1881–89.

46.

Wang

Chen

Zuo

Liu

Sun

. Enhanced renoprotective effect of GDNF-modified adipose-derived mesenchymal stem cells on renal interstitial fibrosis. Stem Cell Res Ther. 2021;12(1):27.

47.

Serejo

TRT

Silva-Carvalho

Braga

Neves

FAR

Pereira

Carvalho

Saldanha-Araujo

. Assessment of the immunosuppressive potential of INF-gamma licensed adipose mesenchymal stem cells, their secretome and extracellular vesicles. Cells. 2019;8(1):22.

48.

McGuirk

Smith

Divine

Zuniga

Weiss

. Wharton’s jelly-derived mesenchymal stromal cells as a promising cellular therapeutic strategy for the management of graft-versus-host disease. Pharmaceuticals (Basel). 2015; 8(2):196–220.

49.

Najar

Raicevic

Boufker

Fayyad Kazan

De Bruyn

Meuleman

Bron

Toungouz

Lagneaux

. Mesenchymal stromal cells use PGE2 to modulate activation and proliferation of lymphocyte subsets: combined comparison of adipose tissue, Wharton’s Jelly and bone marrow sources. Cell Immunol. 2010;264(2):171–79.

50.

Zhang

Huang

Liu

Cong

Chen

Shi

Wang

, et al. Clearance of apoptotic cells by mesenchymal stem cells contributes to immunosuppression via PGE2. Ebiomedicine. 2019;45:341–50.

51.

Yuan

Qin

Wang

Zhang

Tang

Gao

Chen

Sun

. Mesenchymal stem cell therapy induces FLT3L and CD1c(+) dendritic cells in systemic lupus erythematosus patients. Nat Commun. 2019;10(1):2498.

52.

Chun

Tian

Zhang

. Transplantation of mesenchymal stem cells ameliorates systemic lupus erythematosus and upregulates B10 cells through TGF-beta1. Stem Cell Res Ther. 2021;12(1):512.

53.

Carrion

Nova

Ruiz

Diaz

Inostroza

Rojo

Mönckeberg

Figueroa

. Autologous mesenchymal stem cell treatment increased T regulatory cells with no effect on disease activity in two systemic lupus erythematosus patients. Lupus. 2010;19(3):317–22.

54.

Deng

Zhang

Guo

Lim

. A randomised double-blind, placebo-controlled trial of allogeneic umbilical cord-derived mesenchymal stem cell for lupus nephritis. Ann Rheum Dis. 2017;76(8):1436–39.

55.

Barbado

Tabera

Sánchez

García-Sancho

. Therapeutic potential of allogeneic mesenchymal stromal cells transplantation for lupus nephritis. Lupus. 2018;27(13):2161–65.

56.

Wang

Zhang

Liang

Feng

Wang

Hua

Liu

Gilkeson

Silver

, et al. Allogeneic mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus: 4 years of experience. Cell Transplant. 2013;22(12):2267–77.

57.

Yang

Pan

Zhou

Song

Chen

Wang

Chen

. [Therapeutic effects of umbilical cord mesenchymal stem cells transplantation on systemic lupus erythematosus]. Sichuan Da Xue Xue Bao Yi Xue Ban. 2014;45(2):338–41, 350.

58.

Liu

Shi

Zhang

Feng

Guo

Shi

Gao

Chen

Sun

. Mesenchymal stem cells control complement C5 activation by factor H in lupus nephritis. Ebiomedicine. 2018;32:21–30.

59.

Cheng

Ding

Liu

Sun

. Human umbilical cord-derived mesenchymal stem cell therapy ameliorates lupus through increasing CD4+ T cell senescence via MiR-199a-5p/Sirt1/p53 axis. Theranostics. 2021;11(2):893–905.

60.

Chen

Wei

Sun

Zhang

Yang

Tao

Nong

. Exosomes derived from human umbilical cord mesenchymal stem cells regulate macrophage polarization to attenuate systemic lupus erythematosus-associated diffuse alveolar hemorrhage in mice. Int J Stem Cells. 2021;14(3):331–40.

61.

Wang

Zhao

Yang

Wang

Deng

Zhao

Luo

Wei

Guan

Gao

, et al. Extracellular vesicles released from human umbilical cord-derived mesenchymal stromal cells prevent life-threatening acute graft-versus-host disease in a mouse model of allogeneic hematopoietic stem cell transplantation. Stem Cells Dev. 2016;25(24):1874–83.

62.

Wang

Zhang

Chen

Jiang

Shi

Sun

. Umbilical cord mesenchymal stem cell transplantation in active and refractory systemic lupus erythematosus: a multicenter clinical study. Arthritis Res Ther. 2014;16(2):R79.

63.

Zhang

Shi

Liu

Uyanne

Shi

. Mesenchymal stem cells derived from human gingiva are capable of immunomodulatory functions and ameliorate inflammation-related tissue destruction in experimental colitis. J Immunol. 2009;183(12):7787–98.

64.

Akintoye

Lam

Shi

Brahim

Collins

Robey

. Skeletal site-specific characterization of orofacial and iliac crest human bone marrow stromal cells in same individuals. Bone. 2006;38(6):758–68.

65.

Huang

Chen

Yuan

Xue

Dang

Wang

Zadeh

, et al. Human gingiva-derived mesenchymal stem cells inhibit xeno-graft-versus-host disease via CD39-CD73-adenosine and IDO signals. Front Immunol. 2017;8:68.

66.

Zhang

Huang

Dang

Yuan

Wang

Zeng

Sun

Liu

Tan

, et al. Human gingiva-derived mesenchymal stem cells modulate monocytes/macrophages and alleviate atherosclerosis. Front Immunol. 2018;9:878.

67.

Wang

Meng

Liu

Fan

Lipkind

Wang

. Role of gingival mesenchymal stem cell exosomes in macrophage polarization under inflammatory conditions. Int Immunopharmacol. 2020;81:106030.

68.

Zhang

Zhou

Dang

Zhang

Wang

Chen

Liang

Yuan

Chen

, et al. Human gingiva-derived mesenchymal stem cells ameliorate streptozoticin-induced T1DM in mice via suppression of T effector cells and up-regulating Treg subsets. Sci Rep. 2017;7(1):15249.

69.

Dang

Liu

Wang

Huang

Zheng

Sun

Bellanti

, et al. Human gingiva-derived mesenchymal stem cells are therapeutic in lupus nephritis through targeting of CD39(-)CD73 signaling pathway. J Autoimmun. 2020;113:102491.

70.

Shi

Zeng

Shi

Giannakopoulos

Zhang

. Extracellular vesicles of GMSCs alleviate aging-related cell senescence. J Dent Res. 2021;100(3):283–92.

71.

Zayat

Mahmoud

Md Yusof

Mukherjee

D’Agostino

Hensor

EMA

Wakefield

Conaghan

Edwards

Emery

Vital

. Defining inflammatory musculoskeletal manifestations in systemic lupus erythematosus. Rheumatology (Oxford). 2019;58(2):304–12.

72.

Sippl

Faustini

Rönnelid

Turcinov

Chemin

Gunnarsson

Malmström

. Arthritis in systemic lupus erythematosus is characterized by local IL-17A and IL-6 expression in synovial fluid. Clin Exp Immunol. 2021;205(1):44–52.

73.

De Bari

Dell’Accio

Vandenabeele

Vermeesch

Raymackers

Luyten

. Skeletal muscle repair by adult human mesenchymal stem cells from synovial membrane. J Cell Biol. 2003;160(6):909–18.

74.

De Bari

Dell’Accio

Tylzanowski

Luyten

. Multipotent mesenchymal stem cells from adult human synovial membrane. Arthritis Rheum. 2001;44(8):1928–42.

75.

Yan

Liu

Dang

Huang

Yang

. Intra-articular injection of human synovial membrane-derived mesenchymal stem cells in murine collagen-induced arthritis: assessment of immunomodulatory capacity in vivo. Stem Cells Int. 2017; 2017:9198328.

76.

Qiu

Liu

. MiR-129-5p shuttled by human synovial mesenchymal stem cell-derived exosomes relieves IL-1beta induced osteoarthritis via targeting HMGB1. Life Sci. 2021;269:118987.

77.

Liu

Son

Diamond

. HMGB1 in systemic lupus erythematosus. Front Immunol. 2020;11:1057.

78.

Guo

Tao

Yin

Sheng

Zhang

. Exosomes from human synovial-derived mesenchymal stem cells prevent glucocorticoid-induced osteonecrosis of the femoral head in the rat. Int J Biol Sci. 2016;12(10):1262–72.

79.

Yan

Chen

Zhao

Liu

Pan

Lin

Pei

Yang

. Synovium stem cell-derived matrix enhances anti-inflammatory properties of rabbit articular chondrocytes via the SIRT1 pathway. Mater Sci Eng C Mater Biol Appl. 2020;106:110286.

80.

Collins

Molano

Ruiz

Sun

Gilkeson

. Differential efficacy of human mesenchymal stem cells based on source of origin. J Immunol. 2014;193(9):4381–90.

81.

Cheng

Xiong

Pan

Zhang

Zhao

Liu

Marion

. Mesenchymal stem cells: allogeneic MSC may be immunosuppressive but autologous MSC are dysfunctional in lupus patients. Front Cell Dev Biol. 2019;7:285.

82.

Geng

Tang

Zhou

Wang

Yao

Chen

Gao

Chen

Shi

Shen

, et al. MicroRNA-663 induces immune dysregulation by inhibiting TGF-beta1 production in bone marrow-derived mesenchymal stem cells in patients with systemic lupus erythematosus. Cell Mol Immunol. 2019; 16(3):260–74.

83.

Duan

Dou

Feng

Nan

Zhang

. MiR-153-3p induces immune dysregulation by inhibiting PELI1 expression in umbilical cord-derived mesenchymal stem cells in patients with systemic lupus erythematosus. Autoimmunity. 2020;53(4):201–209.

84.

Geng

Tang

Wang

Sun

Wang

Tsao

Feng

Sun

. Reduced Let-7f in bone marrow-derived mesenchymal stem cells triggers Treg/Th17 imbalance in patients with systemic lupus erythematosus. Front Immunol. 2020;11:233.

85.

Gao

Bird

Meednu

Dauenhauer

Liesveld

Anolik

Looney

. Bone marrow-derived mesenchymal stem cells from patients with systemic lupus erythematosus have a senescence-associated secretory phenotype mediated by a mitochondrial antiviral signaling protein-interferon-beta feedback loop. Arthritis Rheumatol. 2017;69(8):1623–35.

86.

Tan

Feng

Meng

Guo

Xia

Zhu

Shi

Cheng

. Rapamycin reverses the senescent phenotype and improves immunoregulation of mesenchymal stem cells from MRL/lpr mice and systemic lupus erythematosus patients through inhibition of the mTOR signaling pathway. Aging (Albany NY). 2016;8(5):1102–14.

87.

Dong

Zhu

Yang

Kong

Zhang

Bao

Zhao

Sha

, et al. Targeting HMGB1 by ethyl pyruvate ameliorates systemic lupus erythematosus and reverses the senescent phenotype of bone marrow-mesenchymal stem cells. Aging (Albany NY). 2019;11(13):4338–53.

88.

Yan

Zhang

Yang

Wang

Liu

. Acetylsalicylic acid rescues the immunomodulation of inflamed gingiva-derived mesenchymal stem cells via upregulating FasL in mice. Stem Cell Res Ther. 2019;10(1):368.

89.

Mai

Zou

Tian

Liao

Luan

Han

Wei

Kuang

Yang

, et al. Double-edged effect of hydroxychloroquine on human umbilical cord-derived mesenchymal stem cells treating lupus nephritis in MRL/lpr mice. Mol Pharm. 2018;15(5):1800–13.

90.

Lee

Kim

Pyo

Park

Jang

Jun

Lee

Kim

Bae

Kim

Hong

, et al. Phorbol ester activates human mesenchymal stem cells to inhibit B cells and ameliorate lupus symptoms in MRL.Fas(lpr) mice. Theranostics. 2020;10(22):10186–99.

91.

Jang

Lee

Hong

Kwok

Cho

Park

. Metformin enhances the immunomodulatory potential of adipose-derived mesenchymal stem cells through STAT1 in an animal model of lupus. Rheumatology (Oxford). 2020;59(6): 1426–38.

92.

Tago

Kobayashi

Ogura

Wada

Yamaguchi

Hayashi

Nakaishi

Kubo

Ueda

. Human amnion-derived mesenchymal stem cells attenuate xenogeneic graft-versus-host disease by preventing T cell activation and proliferation. Sci Rep. 2021;11(1):2406.

93.

Hajkova

Hermankova

Javorkova

Bohacova

Zajicova

Holan

Krulova

. Mesenchymal stem cells attenuate the adverse effects of immunosuppressive drugs on distinct T cell subopulations. Stem Cell Rev Rep. 2017;13(1):104–15.

94.

Chen

Lian

Huang

Lai

Huang

. Additive therapeutic effects of mesenchymal stem cells and IL-37 for systemic lupus erythematosus. J Am Soc Nephrol. 2020;31(1):54–65.

95.

Tan

Shen

Jiang

Meng

Liu

Tao

Cheng

. PTEN/Akt-p27(kip1) signaling promote the BM-MSCs senescence and apoptosis in SLE patients. J Cell Biochem. 2015;116(8):1583–94.

96.

Tan

Leng

Zou

Chen

Min

Zhou

Zhang

. Let-7f-5p ameliorates inflammation by targeting NLRP3 in bone marrow-derived mesenchymal stem cells in patients with systemic lupus erythematosus. Biomed Pharmacother. 2019;118:109313.

97.

Lee

Luk

Korevaar

Koch

Baan

Merino

Hoogduijn

. The importance of dosing, timing, and (in)activation of adipose tissue-derived mesenchymal stromal cells on their immunomodulatory effects. Stem Cells Dev. 2020;29(1):38–48.

98.

Sharma

Hampton

Valiente

Wada

Steigelman

Young

Spurbeck

Blazek

Bösh

Jarjour

Young

. Therapeutic development of mesenchymal stem cells or their extracellular vesicles to inhibit autoimmune-mediated inflammatory processes in systemic lupus erythematosus. Front Immunol. 2017;8:526.

99.

Corbett

Taatizadeh

Tasnim

Little

Garnis

Daugaard

Guns

Hoorfar

ITS

. Challenges and opportunities in exosome research —perspectives from biology, engineering, and cancer therapy. APL Bioeng. 2019;3(1):011503.

100.

Fan

Sun

Khan

. MicroRNAs in extracellular vesicles: sorting mechanisms, diagnostic value, isolation, and detection technology. Front Bioeng Biotechnol. 2022;10:948959.

101.

Gowen

Shahjin

Chand

Odegaard

Yelamanchili

. Mesenchymal stem cell-derived extracellular vesicles: challenges in clinical applications. Front Cell Dev Biol. 2020;8:149.

102.

Xiang

Chen

Cong

Yang

Liu

Qiu

Yang

Wang

Zhang

, et al. Exosomes derived from human urine-derived stem cells inhibit intervertebral disc degeneration by ameliorating endoplasmic reticulum stress. Oxid Med Cell Longev. 2020;2020:6697577.

103.

Wan

Zhao

Gao

Dong

Zhao

Wei

Yang

Xing

Liu

. Mononuclear phagocyte system blockade improves therapeutic exosome delivery to the myocardium. Theranostics. 2020;10(1):218–30.

104.

Liu

Chen

Yin

Xie

. Therapeutic prospects of MicroRNAs carried by mesenchymal stem cells-derived extracellular vesicles in autoimmune diseases. Life Sci. 2021; 277:119458.

105.

Momen-Heravi

Bala

Bukong

Szabo

. Exosome-mediated delivery of functionally active miRNA-155 inhibitor to macrophages. Nanomedicine. 2014;10(7):1517–27.

106.

Elshaer

Bahram

Rajashekar

Gangaraju

El-Remessy

. Modulation of mesenchymal stem cells for enhanced therapeutic utility in ischemic vascular diseases. Int J Mol Sci. 2021;23(1):249.

107.

Matheakakis

Batsali

Papadaki

Pontikoglou

. Therapeutic implications of mesenchymal stromal cells and their extracellular vesicles in autoimmune diseases: from biology to clinical applications. Int J Mol Sci. 2021;22(18):10132.

Current Progress in Treating Systemic Lupus Erythematosus Using Exosomes/MicroRNAs

Abstract

Keywords

Introduction

Mesenchymal Stromal Cells

Anti-Inflammatory and Restorative Functions of MSCs

Immunoregulatory Properties of MSCs

Extracellular Vesicles Released From MSCs

Diagnostic Value of Exosomes and Their miRNAs

MSCs in SLE Treatment

Allogenic MSC Transplantation in SLE

Bone marrow–derived MSCs and exosomes

Adipose tissue–derived MSCs and exosomes

Umbilical cord–derived MSCs and exosomes

Gingival MSCs and exosomes

Synovium-derived MSCs (SMSCs) and exosomes

Autologous MSC Transplantation in SLE

Application of autologous MSCs

MSC dysfunction in patients with SLE

Conditioned MSCs

Development of Combination Therapy

Prospects and Challenges of Cell-Free Therapy

Conclusions

Footnotes

Acknowledgements

Author Contributions

Availability of Data and Materials

Ethical Approval

Statement of Human and Animal Rights

Statement of Informed Consent

Declaration of Conflicting Interests

Funding

ORCID iD

References