Adiponectin, Mesenchymal Stem Cells and Exosome-Mediated Cardioprotection in Heart Failure

Mesenchymal Stem/Stromal Cells: An Emerging Approach to Tissue Protection and Regeneration

Mesenchymal stem/stromal cells (MSCs) are cultured adult progenitor cells that naturally reside in virtually all tissues of the body. They are widely investigated for their regenerative, immunomodulatory, and tissue-protective properties and have attracted considerable interest in regenerative medicine and cell-based therapeutic research.

MSCs are particularly relevant because of their ability to influence the biological environment of damaged tissues through the release of bioactive molecules and extracellular vesicles. Their therapeutic potential has been investigated in a variety of pathological conditions, including graft-versus-host disease, cardiovascular disorders, type 1 diabetes, and type 2 diabetes.

The administration or transplantation of MSCs has become an important approach in experimental and clinical cell therapy research. However, despite encouraging findings, the therapeutic effectiveness of transplanted MSCs can vary considerably depending on the biological characteristics of the recipient and the surrounding physiological environment.

One important question concerns how circulating factors in the recipient influence the regenerative and protective functions of administered MSCs. Understanding these interactions is essential for improving the effectiveness of cell-based therapies and identifying biological conditions that may enhance their therapeutic potential.

In this context, adiponectin, an adipocyte-derived circulating protein, has emerged as an important regulator of MSC activity. Research has demonstrated that the cardioprotective properties of intravenously administered MSCs in a mouse model of pressure-overload heart failure are strongly influenced by circulating adiponectin levels.

The findings indicate that adiponectin does not simply act as a metabolic hormone but also regulates the therapeutic activity of MSCs by stimulating the production and secretion of exosomes, specialized extracellular vesicles involved in intercellular communication.

Understanding Adiponectin: Structure, Circulating Levels and Biological Functions

Adiponectin is an atypical adipocyte-secreted protein that circulates abundantly in peripheral blood. It is produced almost exclusively by adipocytes and is released into the circulation in several structural forms, including trimers, hexamers, and high-molecular-weight (HMW) multimers.

Among adipocytokines, also known as adipokines, adiponectin is characterized by exceptionally high circulating plasma concentrations. Its abundance and diverse molecular forms reflect its important physiological functions in metabolic regulation, cardiovascular homeostasis, and cellular communication.¹˒²

Human cross-sectional studies have demonstrated an inverse relationship between circulating adiponectin concentrations and body weight or body mass index (BMI).³˒⁴ This association has contributed to the extensive investigation of adiponectin as an important regulator of metabolic and cardiovascular physiology.

Functionally, adiponectin has traditionally been associated with several biological activities mediated through adiponectin receptors (AdipoRs), particularly AdipoR1 and AdipoR2. These receptors participate in metabolic regulation and contribute to the effects of adiponectin on cellular energy metabolism and other physiological processes.

Adiponectin has also been implicated in the opsonization of dead cells through interactions involving calreticulin, demonstrating that its biological functions extend beyond metabolic regulation.⁵

However, adiponectin does not exert all its biological effects through the same molecular pathways. Its different circulating forms, particularly HMW multimers, have attracted considerable attention because of their specific associations with cardiovascular and tissue-protective functions.

High-Molecular-Weight Adiponectin and Its Biological Importance

Adiponectin circulates in different oligomeric forms, with the high-molecular-weight multimer representing an important biologically active form.

Clinical and experimental investigations have identified HMW adiponectin, generally comprising six or more adiponectin subunits, as an important mediator of several pleiotropic physiological effects.⁶˒⁷˒⁸˒⁹

HMW adiponectin is particularly abundant in certain tissues, including the heart, vascular endothelium, and skeletal muscles. Its accumulation within these tissues is associated with its interaction with T-cadherin, a distinctive cell-surface protein involved in adiponectin binding.¹⁰˒¹¹

This tissue distribution is particularly interesting because it provides a mechanism through which circulating adiponectin can influence local cellular functions.

The presence of substantial amounts of HMW adiponectin in cardiovascular and skeletal muscle tissues has been demonstrated to be important for adiponectin-mediated cardiovascular protection and skeletal muscle regeneration.¹³˒¹⁴˒¹⁵˒¹⁶

These observations suggest that adiponectin functions not only as a circulating metabolic factor but also as a regulator of tissue-specific biological responses.

T-Cadherin: A Key Binding Partner of Adiponectin

T-cadherin is a distinctive member of the cadherin family characterized by its attachment to the cell membrane through a glycosylphosphatidylinositol (GPI) anchor.

Unlike conventional transmembrane cadherins, T-cadherin is not directly connected to the intracellular cytoskeleton through a conventional transmembrane domain. Instead, its GPI anchor allows it to associate with the outer surface of the plasma membrane.

T-cadherin has attracted considerable scientific interest because of its ability to bind circulating adiponectin, particularly its HMW multimeric form.

HMW adiponectin is found in significant quantities in tissues expressing T-cadherin, including the heart, vascular endothelium, and skeletal muscle. This interaction contributes to the localization and biological activity of adiponectin within these tissues.

Previous investigations demonstrated that native adiponectin binds to cells expressing T-cadherin, whereas comparable binding was not observed with other proposed adiponectin-binding partners, including AdipoRs and calreticulin, under the investigated conditions.¹²

This finding provides important insight into the distinct functions of adiponectin-binding proteins and suggests that T-cadherin plays a specific role in mediating the tissue distribution of native adiponectin.

T-cadherin is also relevant to the therapeutic properties of MSCs. Proteomic investigations have indicated that T-cadherin is among the most abundantly expressed proteins on the surface of mesenchymal stem/stromal cells.³²

This observation provides a potential molecular link between circulating adiponectin and MSC biological activity.

By binding to T-cadherin expressed on MSCs, adiponectin can stimulate intracellular mechanisms involved in exosome production and secretion, thereby influencing the ability of these cells to communicate with recipient tissues.

Mesenchymal Stem/Stromal Cells and Their Therapeutic Potential

Mesenchymal stem/stromal cells are cultured progenitor cell populations that originate from tissues throughout the body and are considered important contributors to tissue homeostasis.

They have been studied extensively because of their ability to influence immune responses, regulate inflammation, and support tissue repair through different paracrine mechanisms.¹⁷˒¹⁸

Unlike approaches that rely exclusively on the replacement of damaged cells, MSC-based therapies can exert beneficial effects through the release of biological mediators that influence the activity of surrounding cells.

The therapeutic potential of MSCs has been investigated in several diseases and experimental conditions, including:

• Graft-versus-host disease: MSCs have been investigated for their immunomodulatory properties and their potential to regulate pathological immune responses.¹⁹

• Heart disease: MSC administration has been studied for its potential to protect cardiac tissue and support functional recovery following cardiovascular injury.²⁰

• Type 1 diabetes: Their immunomodulatory and regenerative properties have generated interest in investigations of pancreatic and immune-related mechanisms.²¹

• Type 2 diabetes: MSCs have also been explored in research involving metabolic regulation and tissue protection.²²

According to the clinical trials database cited in the original study, more than 893 clinical trials had investigated the use of MSCs for the treatment of different diseases.²³

Despite the growing interest in MSC-based therapies, their therapeutic effectiveness remains influenced by several biological factors.

One important limitation is the incomplete understanding of how characteristics of the recipient influence the activity of transplanted cells.

The recipient's circulating environment may contain hormones, proteins, inflammatory mediators, and metabolic factors capable of modifying the behavior of administered MSCs.

Consequently, identifying the molecules that regulate MSC activity could provide new opportunities to improve cell therapy outcomes.

Adiponectin represents one such factor because of its ability to interact with T-cadherin expressed on MSCs and stimulate their exosome-mediated biological functions.

Exosomes: Specialized Extracellular Vesicles Involved in Cell-to-Cell Communication

Exosomes are small extracellular vesicles of endosomal origin, generally measuring approximately 50–150 nm in diameter. They are surrounded by a lipid bilayer and are generated through a specialized intracellular process involving endosomal membrane remodeling.

Their formation begins within the endocytic pathway, where the membrane of an endosome undergoes inward budding. This process generates intraluminal vesicles within structures known as multivesicular bodies (MVBs).

Multivesicular bodies can subsequently follow different intracellular pathways. They may fuse with lysosomes, leading to the degradation of their contents, or fuse with the plasma membrane, resulting in the release of intraluminal vesicles into the extracellular environment.

Once released, these vesicles are referred to as exosomes.

Exosomal release is therefore associated with the endosomal system and represents a pathway for transferring selected cellular components outside the producing cell.

Exosome Biogenesis and Cellular Release

The production of exosomes involves coordinated molecular mechanisms responsible for membrane remodeling, vesicle formation, and intracellular sorting.

One important pathway involves the ESCRT complex, or endosomal sorting complex required for transport.

ESCRT-associated mechanisms participate in the organization of endosomal membranes and the formation of intraluminal vesicles within multivesicular bodies.

These processes are essential for generating exosomes that can subsequently be released through fusion of multivesicular bodies with the plasma membrane.

The resulting vesicles contain selected molecular components derived from the parent cell, including proteins, lipids, messenger RNAs (mRNAs), and small non-coding RNAs.

The composition of exosomes reflects, at least in part, the biological characteristics and physiological state of the cells from which they originate.

Exosomes as Mediators of Intercellular Communication

Beyond their role in cellular waste disposal, exosomes are recognized as important mediators of cell-to-cell communication under both physiological and pathological conditions.

By transferring proteins, lipids, mRNAs, and small non-coding RNAs, exosomes can influence the biological activities of recipient cells.

These extracellular vesicles can be detected in different biological fluids and provide a mechanism for transferring molecular information between cells and tissues.²⁴˒²⁵˒²⁶

Their involvement in intercellular communication has also been associated with different metabolic regulatory pathways.²⁷

Stem-cell-derived exosomes are particularly interesting because they can reproduce some of the biological effects associated with their parent cells.

Research suggests that MSC-derived exosomes can contribute to organ protection through different mechanisms, including modulation of the immune functions of recipient cells²⁸ and stimulation of tissue repair processes.²⁹˒³⁰˒³¹

These findings have expanded the investigation of MSC-based therapies beyond the direct transplantation of whole cells and toward the biological functions of the extracellular vesicles they release.

Adiponectin Stimulates Exosome Biogenesis and Secretion Through T-Cadherin

Previous research has demonstrated that adiponectin can directly influence exosome production and secretion.

In earlier investigations, a new one-step purification method was developed to isolate clinically important multimeric forms of adiponectin from serum.¹¹

Adiponectin obtained through this purification procedure was subsequently shown to enhance exosome biogenesis and secretion.²⁷˒³³

Further experimental evidence indicated that circulating exosome levels in peripheral blood were influenced by adiponectin expression in vivo.

Genetic loss of adiponectin reduced systemic exosome levels, whereas adiponectin overexpression increased their abundance in the peripheral circulation.²⁷˒³³

These observations suggest that adiponectin contributes to the regulation of extracellular vesicle production at the systemic level.

T-Cadherin-Dependent Regulation of Exosome Production

The stimulation of exosome biogenesis by adiponectin requires the presence of T-cadherin.

Previous studies demonstrated that adiponectin-induced exosome production depends on T-cadherin expression rather than the classical adiponectin receptors AdipoR1 and AdipoR2.¹⁶˒²⁷˒³³

This distinction is important because it identifies a specific molecular pathway through which adiponectin can regulate extracellular vesicle production.

The interaction between adiponectin and T-cadherin may therefore contribute to the regulation of cellular processes associated with multivesicular body formation, intraluminal vesicle generation, and exosome secretion.

Adiponectin-induced exosome stimulation has also been observed in muscle cells, where it was associated with improved skeletal muscle regeneration.¹⁶˒²⁷

These findings suggest that the interaction between adiponectin and T-cadherin may represent a broader mechanism involved in tissue protection and regeneration.

Adiponectin and the Cardioprotective Effects of Mesenchymal Stem Cells

The relationship between adiponectin, T-cadherin, and exosome production provides an important framework for understanding how MSCs exert their therapeutic effects.

The present study was designed to investigate the role of adiponectin in the beneficial effects of human adipose tissue-derived mesenchymal stem cells (hMSCs) in heart failure.

The researchers focused on a mouse model of pressure-overload heart failure, in which increased cardiac workload produces ventricular hypertrophy and subsequent impairment of cardiac function.

In this experimental model, systemic administration of hMSCs improved left ventricular cardiac function.

However, the cardioprotective effects of the injected cells were not independent of the recipient's physiological environment.

Instead, their therapeutic efficacy largely depended on three interconnected biological components:

1. The availability of circulating adiponectin in recipient mice.

2. The expression of T-cadherin by administered hMSCs.

3. The production of exosomes by hMSCs through mechanisms involving the ESCRT pathway.

These findings indicate that MSC-mediated cardioprotection is influenced not only by the properties of the transplanted cells but also by specific circulating factors present in the recipient.

Human Adipose Tissue-Derived MSCs and Cardiac Protection

Human adipose tissue-derived mesenchymal stem cells were used to investigate the effects of systemic MSC administration in a mouse model of pressure-overload-induced cardiac dysfunction.

Adipose tissue represents an important source of MSC populations used in experimental research and cell-based therapeutic investigations.

Following intravenous administration, hMSCs exerted beneficial effects on left ventricular function in the investigated animal model.

Interestingly, these cardioprotective effects were closely associated with the ability of MSCs to produce and release exosomes.

Rather than functioning exclusively through direct cellular replacement, the injected MSCs acted through extracellular vesicles that could mediate interactions with recipient tissues.

This observation supports the importance of paracrine mechanisms in understanding the therapeutic activities of transplanted MSCs.

T-Cadherin Expression in MSCs Is Essential for Adiponectin-Mediated Exosome Stimulation

T-cadherin expression on MSCs represents an important component of the proposed mechanism.

Adiponectin binds to T-cadherin on the surface of MSCs and stimulates exosome biogenesis and secretion.

This interaction provides a molecular connection between the circulating environment of the recipient and the secretory activity of the transplanted cells.

When adiponectin is available at sufficient levels, its interaction with T-cadherin promotes the production and release of exosomes.

These vesicles can subsequently influence recipient cells through the transfer of biologically active molecular components.

Consequently, the expression of T-cadherin by MSCs is not merely a structural characteristic but an important factor associated with their adiponectin-dependent therapeutic activity.

ESCRT-Mediated Exosome Production

The endosomal sorting complex required for transport (ESCRT) participates in the formation of intraluminal vesicles within multivesicular bodies.

In the investigated model, the cardioprotective effects of hMSCs depended on ESCRT-mediated exosome production.

This observation highlights the importance of intracellular vesicle biogenesis mechanisms in the therapeutic activity of MSCs.

By regulating the formation of exosomes, ESCRT-associated pathways contribute to the release of extracellular vesicles involved in communication between transplanted cells and recipient tissues.

The results therefore connect three levels of biological regulation:

• Circulating adiponectin availability.

• T-cadherin-dependent stimulation of MSCs.

• ESCRT-mediated exosome production and secretion.

Together, these mechanisms help explain how recipient-derived circulating factors can influence the protective activity of transplanted stem/stromal cells.

Increasing Circulating Adiponectin to Enhance MSC Therapeutic Efficacy

An additional important aspect of the study involved investigating whether increasing circulating adiponectin could improve the cardioprotective effects of administered MSCs.

Two different experimental strategies were used to increase plasma adiponectin levels.

Pharmacological Stimulation Through PPARγ Agonists

Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor involved in adipocyte differentiation, lipid metabolism, and metabolic regulation.

PPARγ activation can influence adiponectin expression and circulating concentrations.

In the investigated study, treatment with a PPARγ agonist increased plasma adiponectin levels and enhanced the cardioprotective effects of MSC administration.

This finding suggests that pharmacological modulation of adiponectin availability may represent a potential strategy for improving the therapeutic activity of MSCs.

Adenovirus-Mediated Adiponectin Overexpression

A second approach involved the use of adenoviral gene delivery to increase adiponectin expression.

Adenovirus-mediated overexpression was used to enhance systemic adiponectin levels in the experimental animals.

This genetic approach also increased plasma adiponectin concentrations and improved MSC-induced cardioprotection.

The results obtained using both pharmacological and genetic approaches support the relationship between circulating adiponectin availability and MSC therapeutic efficacy.

Adiponectin Knockout Mice: Evidence for the Importance of Circulating Adiponectin

The importance of adiponectin was further investigated using adiponectin knockout (AKO) mice.

These animals lack endogenous adiponectin expression, providing an experimental model for assessing the contribution of this circulating factor to MSC-mediated tissue protection.

In adiponectin knockout mice, the cardioprotective effects observed following MSC administration were not achieved.

This result provides important evidence that adiponectin is a necessary component of the therapeutic mechanism investigated in the study.

The comparison between normal mice, animals receiving adiponectin-enhancing interventions, and adiponectin knockout mice demonstrates the importance of the recipient's circulating adiponectin environment.

It also reinforces the proposed interaction between adiponectin, T-cadherin expression on MSCs, and exosome-mediated cardioprotection.

Proposed Molecular Mechanism: From Adiponectin Binding to Cardiac Protection

The findings can be integrated into a molecular pathway connecting circulating adiponectin with the biological activities of transplanted MSCs.

The mechanism involves several sequential events:

1. Circulating adiponectin availability

Adiponectin is secreted by adipocytes and circulates in different multimeric forms, including HMW adiponectin.

2. Interaction with T-cadherin

Circulating adiponectin binds to T-cadherin expressed on the surface of administered mesenchymal stem/stromal cells.

3. Stimulation of exosome biogenesis

Adiponectin-T-cadherin interaction promotes intracellular mechanisms associated with exosome production.

4. ESCRT-dependent vesicle formation

The endosomal sorting complex required for transport participates in the formation of intraluminal vesicles within multivesicular bodies.

5. Exosome secretion

Multivesicular bodies release exosomes into the extracellular environment through fusion with the plasma membrane.

6. Communication with recipient tissues

MSC-derived exosomes transfer biological molecules that can influence the activity of recipient cells and contribute to tissue-protective responses.

7. Cardioprotection

In the pressure-overload heart failure model, these exosome-mediated effects are associated with improved left ventricular cardiac function following systemic hMSC administration.

This proposed mechanism demonstrates how a circulating adipocyte-derived factor can regulate the therapeutic activity of transplanted progenitor cells through extracellular vesicle signaling.

Biological and Therapeutic Significance of the Findings

The findings provide new insights into the mechanisms responsible for MSC-mediated organ protection.

Traditionally, many investigations have focused on the intrinsic properties of transplanted MSCs, including their differentiation potential, immunomodulatory activity, and capacity to release paracrine factors.

However, this study highlights the importance of the recipient's systemic environment in determining the effectiveness of cell-based therapies.

Adiponectin emerges as an important regulator of this interaction because it influences MSC exosome production through T-cadherin-dependent mechanisms.

The relationship between adiponectin and MSC-derived exosomes also provides a possible explanation for differences in therapeutic responses between recipients with different circulating adiponectin levels.

Furthermore, the improvement of MSC-mediated cardioprotection following pharmacological or adenovirus-mediated elevation of adiponectin suggests that modifying the recipient environment may represent a potential strategy for enhancing cell therapy.

These findings are particularly relevant to regenerative medicine, cardiovascular research, extracellular vesicle biology, and the development of therapeutic approaches based on stem-cell-derived products.

Nevertheless, the results were obtained in an experimental mouse model of pressure-overload heart failure. Further investigation is required to establish how these mechanisms translate into clinical settings and whether increasing adiponectin can improve the outcomes of MSC-based therapies in humans.

Conclusion

The interaction between adiponectin, T-cadherin, and mesenchymal stem/stromal cells reveals an important mechanism regulating exosome-mediated organ protection.

Adiponectin stimulates exosome biogenesis and secretion by binding to T-cadherin expressed on MSCs. This process involves ESCRT-dependent vesicle production and contributes to the cardioprotective effects of intravenously administered hMSCs in a mouse model of pressure-overload heart failure.

The enhancement of plasma adiponectin levels through PPARγ agonist treatment or adenovirus-mediated overexpression further increased the therapeutic efficacy of MSCs, whereas the absence of adiponectin in knockout mice was associated with a lack of the observed cardioprotective response.

Overall, these findings demonstrate that circulating adiponectin is an important determinant of MSC therapeutic activity and provide new perspectives on the regulation of stem-cell-derived exosomes in cardiovascular protection.

Understanding the molecular relationship between adiponectin, T-cadherin, and extracellular vesicle production may contribute to the development of improved regenerative medicine strategies and more effective cell-based therapeutic approaches.

Keywords

Adiponectin, Exosome, Extracellular Vesicle, Mesenchymal Stem/Stromal Cells, MSCs, Heart Failure, TAC Model, T-Cadherin, Exosome Biogenesis, ESCRT, Cardioprotection, PPARγ, Stem Cell Therapy, Extracellular Vesicle Secretion, Pressure-Overload Heart Failure.