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DOI: 10.1039/D4TB00778F (Review Article) J. Mater. Chem. B, 2024, Advance Article

Exogenous MSC based tissue regeneration: a review of immuno-protection strategies from biomaterial scaffolds

Rongbai Juabc, Xinhui Gaoabc, Chi Zhangabc, Wei Tangc, Weidong Tian*abc and Min He*abc
aEngineering Research Center of Oral Translational Medicine, Ministry of Education, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China. E-mail: drtwd@sina.com
bNational Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
cState Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China

Received 9th April 2024 , Accepted 1st July 2024

First published on 15th July 2024

Abstract

Mesenchymal stem cell (MSC)-based tissue engineering holds great potential for regenerative medicine as a means of replacing damaged or lost tissues to restore their structure and function. However, the efficacy of MSC-based regeneration is frequently limited by the low survival rate and limited survival time of transplanted MSCs. Despite the inherent immune privileges of MSCs, such as low expression of major histocompatibility complex antigens, tolerogenic properties, local immunosuppressive microenvironment creation, and induction of immune tolerance, immune rejection remains a major obstacle to their survival and regenerative potential. Evidence suggests that immune protection strategies can enhance MSC therapeutic efficacy by prolonging their survival and maintaining their biological functions. Among various immune protection strategies, biomaterial-based scaffolds or cell encapsulation systems that mediate the interaction between transplanted MSCs and the host immune system or spatially isolate MSCs from the immune system for a specific time period have shown great promise. In this review, we provide a comprehensive overview of these biomaterial-based immune protection strategies employed for exogenous MSCs, highlighting the crucial role of modulating the immune microenvironment. Each strategy is critically examined, discussing its strengths, limitations, and potential applications in MSC-based tissue engineering. By elucidating the mechanisms behind immune rejection and exploring immune protection strategies, we aim to address the challenges faced by MSC-based tissue engineering and pave the way for enhancing the therapeutic outcomes of MSC therapies. The insights gained from this review will contribute to the development of more effective strategies to protect transplanted MSCs from immune rejection and enable their successful application in regenerative medicine.

1. Introduction

Tissue regeneration, the process of replacing damaged or lost tissues to restore their structure and function, has been a long-standing goal in the field of regenerative medicine.1 Exogenous mesenchymal stem cells (MSCs), due to their ability to self-renew and differentiate into various cell types, have sparked significant interest as a potential solution for tissue regeneration.2,3 For the ease of accessibility and relative abundance, bone marrow MSCs (BMMSCs), adipose-derived MSCs (ADMSCs), dental stem cells (DSCs), stem cells from human exfoliated deciduous teeth (SHED), and stem cells from the apical papilla (SCAP) have emerged as attractive cell sources for bone, soft tissue, or dental regeneration.4 Various studies, via animal models and clinical trials, have demonstrated that exogenous MSCs hold great promise in tissue engineering, especially in bone and dental regeneration. In addition to self-renewal and multiple differentiation potential, the ability of MSCs to affect the function of other cells and to regulate the systemic immune environment via paracrine or cell–cell cross-talking also contributes to their therapeutic efficacy.5 Nevertheless, the efficacy of MSC-based regeneration is not always fulfilled due to their limited survival rate after transplantation into the recipients. Many tracking studies of implanted MSCs indicated that surviving MSCs reduced to only 15% of the initial number of transplanted cells within several days.6 Research has shown that whether exogenous MSCs promote tissue regeneration by compensating for the insufficient number of endogenous MSCs or by modulating the local immune microenvironment, improving their survival rate and prolonging their survival time after implantation, both contribute to improving their therapeutic effect.7

Among numerous factors that inducing low survival rates of MSCs, such as lack of suitable niche, improper delivery methods, and inadequate vascularization, immune rejection is considered as the main challenge. Despite MSCs being recognized as immune-privileged due to their low expression of the major histocompatibility complex (MHC) and their immunoregulatory capacity, MSC transplantation can also induce the activation of an immune rejection, leading to fast apoptosis, death, and clearance of the transplanted MSCs.8 After being recognized by the immune system, various immune cells including neutrophils, monocytes/macrophages, natural killer cells, dendritic cells, and T-lymphocytes will be activated, interacting with exogenous MSCs via direct cell-to-cell contact or secreting pro-inflammatory cytokines, finally generating a diseased immune micro-environment to impair MSC viability and differentiation.9,10 For example, the immune response caused by the engraftment of exogenous MSCs would induce over-production of reactive oxygen species (ROS), leading to local oxidative stress. The excessive ROS can damage the structure of DNA and proteins, activate stress-related signaling pathways, disrupt the mitochondrial membrane, and impair ATP production, finally resulting in cell apoptosis and death.11,12 Therefore, establishing effective MSC-based approaches for tissue regeneration remains a tremendous challenge, especially considering the adverse effects of immune rejection.13

To enhance the MSC survival and therapeutic efficacy, extensive research has focused on developing strategies to protect exogenous MSCs from immune rejection.14,15 For example, administration of immunosuppressive drugs has been demonstrated to be able to improve the MSC survival rate by suppressing the immune system's activity and preventing the recognition and attacking the transplanted cells.16 A genetic modification technique was also attempted to alter MSCs’ immunogenicity, making them less recognizable by the recipient's immune system.17 Despite the use of biomaterial scaffolds to culture and deliver MSCs demonstrating their advantage in maintaining MSC biological functions, it is only recently that researchers have begun to explore their potential to modulate the immune micro-environment, targeting on manipulating a favorable immune environment for MSC survival.18 In terms of immune protection of exogenous MSCs using biomaterial scaffolds, improvements can be made in modifying the chemical structure of the matrix, designing specific microstructural features of the scaffold, loading immunomodulatory drugs and regulating their release to mediate the interaction between the cell-laden scaffold and the host immune system.19 Additionally, cell encapsulation systems based on hydrogel scaffolds can physically isolate exogenous MSCs from direct contact with the host immune system, thereby attenuating immune rejection.20 This review provides a comprehensive overview of the biomaterial-based immune protection strategies employed for exogenous MSCs, and each strategy will be critically examined, highlighting the strengths, limitations, and potential applications in MSC-based tissue engineering.

In this review, we initially provide a general overview of the spatiotemporal dynamics interactions between exogenous MSCs and the host immune system. The following section briefly addresses how the host immune system attacks the transplanted exogenous MSCs. In the later sections, we provide a comprehensive overview of the current scaffold-based immune protection strategies employed for exogenous stem cells. Each strategy will be critically examined, highlighting the strengths, limitations, and potential applications in stem cell transplantation, and the underlying mechanisms through which these immune protection strategies exert their effects will be deeply delved. In conclusion, this comprehensive review will shed light on the current state of knowledge regarding immune protection strategies for exogenous stem cells. Through a thorough analysis of the existing literature, we aim to provide valuable insights and highlight the potential avenues for future research, ultimately paving a new path for enhancing the regenerative potential of stem cells. By overcoming immune rejection, we can unlock the full therapeutic potential of MSC transplantation and enhance the safety, efficacy, and long-term survival of exogenous MSCs, bringing us closer to personalized regenerative medicine.

2. Spatiotemporal interactions between the host immune system and exogenous MSCs

2.1 Immunomodulation property of exogenous MSCs

Many studies have shown that MSCs have the ability to regulate both the innate and adaptive immune responses through direct contact with various immune cells and the secretion of soluble cytokines. These cytokines include prostaglandin E2 (PGE2), indoleamine-2,3-dioxygenase (IDO), nitric oxide, IL-10, and transforming growth factor-beta (TGF-β).21,22 MSCs can effectively influence the behavior of immune cells such as neutrophils, macrophages, dendritic cells, natural killer cells, T cells, and B cells.23,24 This influence includes migration, proliferation, apoptosis, differentiation, polarization, cytokine production, and even cross-talk between different immune cells. By modulating all these aspects of immune cell function, MSCs demonstrate their comprehensive and potent immunomodulatory capacity, as shown in Fig. 1.25,26
image file: d4tb00778f-f1.tif
Fig. 1 Mesenchymal stem cells mainly regulate various immune cells, such as macrophages, neutrophils, dendritic cells, natural killer cells, T cells, and B cells, through paracrine and indirect cellular contact. The secretion group of MSCs includes various cytokines, chemokines and growth factors, and its immune regulatory function depends on the source, target cells, and microenvironment of MSCs.
Effects on neutrophils. Neutrophils are rapidly recruited to the site of injury and play a crucial role as short-term effector cells of the innate immune system.27 They produce antimicrobial substances and proteases to inhibit pathogen growth and also promote the migration and recruitment of other immune cells through the secretion of various cytokines and growth factors. MSCs exert multiple effects on the physiological behavior of neutrophils, including modulation of migration, activation, phagocytosis, apoptosis, cytokine production, and induction of an immunomodulatory phenotype in neutrophils.28 Studies have shown that MSCs can regulate the recruitment and migration of neutrophils through the secretion of factors such as stimulated gene-6 (TSG-6).29 MSCs can also modulate the activation state of neutrophils. When co-cultured with stimulated MSCs, neutrophils exhibit reduced production of reactive oxygen species (ROS) and pro-inflammatory cytokines due to the presence of soluble factors such as IL-6 derived from MSCs. Additionally, MSCs can protect neutrophils by inhibiting their apoptosis, while maintaining their phagocytosis and chemotaxis capabilities.30 Furthermore, MSCs can reduce neutrophil-mediated tissue damage by upregulating extracellular superoxide dismutase (SOD3) and decreasing the concentration of superoxide anions.31 MSCs also modulate the apoptosis of neutrophils by influencing the expression of anti-apoptotic or pro-apoptotic proteins. For instance, MSCs can secrete factors such as granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and stem cell factor (SCF) to activate survival pathways in neutrophils and inhibit apoptotic signals. They can also downregulate the expression of pro-apoptotic proteins, including BCL2 – associated protein X (Bax) and caspases. In addition, MSCs can inhibit neutrophil apoptosis by modulating the inflammatory microenvironment and reducing the levels of pro-inflammatory cytokines that induce neutrophil apoptosis, such as tumor necrosis factor-α (TNF-α) and interleukin-1 beta (IL-1β).32 Moreover, studies have demonstrated that MSC-derived exosomes (MSC-EV) enhance the activity of neutrophils, decrease neutrophil apoptosis, and increase their phagocytic ability, thereby strengthening the body's immune response.33,34 The interaction between MSCs and neutrophils highlights the immunomodulatory potential of MSCs in regulating inflammation and mitigating tissue damage. The beneficial effects of MSCs on neutrophils highlight their significance in therapeutic applications for various inflammatory conditions and immune-related disorders.
Effects on monocytes/macrophages. Macrophages are crucial immune cells that play a pivotal role in the tissue healing process due to their multiple functions and high plasticity.35 Following injury, circulating monocytes infiltrate the site of injury and differentiate into macrophages. These macrophages regulate the entire wound healing process.36 Macrophages can be broadly characterized into two distinct functional phenotypes based on their properties and surface markers: pro-inflammatory M1 and anti-inflammatory M2. Initially, macrophages at the injury site polarize to the pro-inflammatory M1 phenotype, which is involved in the phagocytosis of dead cells and pathogens, as well as the secretion of pro-inflammatory cytokines such as TNF-α, IL-1β, inducible nitric oxide synthase (iNOS), and interleukin-6 (IL-6).37 The M1 phenotype typically dominates the injury site for 3–4 days. Subsequently, macrophages transition to the anti-inflammatory M2 phenotype, which produces anti-inflammatory cytokines like IL-4 and IL-10 to resolve inflammation and secrete pro-healing growth factors that promote cell proliferation, differentiation, and extracellular matrix deposition. During tissue healing, macrophage polarization follows a similar pattern, with an initial dominance of the M1 phenotype and a shift towards the M2 phenotype during the mid to late stages of the repair response. The balance and timing of M1-to-M2 polarization are critical for successful tissue healing. The prolonged presence of the M1 phenotype and failure to transition to the M2 phenotype can impair tissue healing. Therefore, precise control over the M1-to-M2 polarization throughout the tissue regeneration process represents a promising strategy for enhancing tissue regeneration.38,39

Numerous studies have demonstrated that MSCs possess a robust capability to regulate the activity of monocytes and macrophages. This includes their differentiation, polarization, and cytokine production.40–42 Co-culturing MSCs with monocytes leads to a skewing of monocyte differentiation towards the anti-inflammatory M2 macrophage phenotype, with higher concentrations of IL-10 observed in the co-culture supernatants.43 Similarly, macrophages co-cultured with MSCs tend to polarize towards the M2 phenotype, expressing higher levels of M2 surface markers and producing elevated levels of anti-inflammatory cytokines such as IL-4 and IL-10, while displaying lower levels of pro-inflammatory cytokines.44 Moreover, these co-cultured macrophages also exhibit improved phagocytic activity. The capacity of MSCs to modulate macrophage polarization is primarily mediated by the secretion of soluble factors such as indoleamine 2,3-dioxygenase (IDO), C–C motif ligand 18 (CCL-18), TNF-α-stimulated gene-6 protein (TSG-6), and prostaglandin E2 (PGE2).45–48 Studies have shown that MSCs upregulate IDO expression when stimulated by TNF-α and IFN-γ, resulting in the promotion of monocyte differentiation towards M2 macrophages.49 MSCs stimulate macrophages to produce anti-inflammatory cytokines by increasing cyclooxygenase-2 activity and releasing PGE2, which acts on macrophages through prostaglandin receptors.50 Additionally, when MSCs are stimulated by inflammatory signals, they secrete a protein called TSG-6, which interacts with CD44 receptors on macrophages and attenuates the inflammatory cascade through negative feedback on NF-κB signaling.51 Furthermore, MSC-derived exosomes are also capable of promoting the polarization of macrophages towards the M2 phenotype. These exosomes release a secreted proteome consisting of multiple cytokines, chemokines, and extracellular vesicles (EVs) that stimulate M2 polarization.52 In vivo studies have shown that MSC-derived EVs can induce macrophage polarization towards the M2 phenotype by downregulating IL-23, IL-22, IL-6, and Nos2, while upregulating Arg1 and Ym1, which are late markers of alternative activation.53

Studies investigating the mechanism underlying the promotion of macrophage polarization towards the M2 phenotype by MSCs have shown promising results in animal models of tissue injury and inflammatory-related diseases. Administration of MSCs has been found to have beneficial effects on wound healing, brain/spinal cord injuries, as well as diseases affecting the heart, lungs, and kidneys.54,55 These studies have typically observed reduced immune cell infiltration, increased proportions of M2 macrophages, decreased expression of pro-inflammatory cytokines, and increased expression of pro-healing cytokines.56,57 However, further studies focusing on the molecular mechanisms involved in the interaction between MSCs and macrophages are necessary. These studies will not only contribute to a better understanding of MSC biology but also provide valuable insights for optimizing the use of MSCs in clinical practice.

Effects on dendritic cells (DC). Dendritic cells (DCs) play a crucial role in the tissue repair process.58 These specialized antigen-presenting cells capture and process antigens from damaged tissues, initiating immune responses necessary for tissue repair and regeneration. During the initial phase of inflammation, DCs secrete pro-inflammatory cytokines like TNF-α and IL-1β to promote inflammation and recruit immune cells to the site of injury.59 In the middle or late stages, DCs produce anti-inflammatory cytokines such as IL-10 and TGF-β, which aid in resolving inflammation and promoting tissue healing.60 DCs also influence the balance between pro-inflammatory and anti-inflammatory cells by promoting the differentiation of regulatory T cells (Tregs) and inhibiting the activation of effector T cells.61 Moreover, DCs participate in the regulation of wound healing by producing growth factors like VEGF and bFGF, which promote the formation of new blood vessels in injured tissues.62

MSCs have the ability to modulate various aspects of dendritic cell (DC) activity, including maturation, activation, differentiation, antigen presentation, and cytokine production.63–66 They achieve this by downregulating the expressions of co-stimulatory molecules like CD80 and CD86, inhibiting the production of pro-inflammatory cytokines such as IL-12 and IL-23, promoting the expression of immunomodulatory molecules like IDO and programmed death ligand 1 (PD-L1), and enhancing the production of anti-inflammatory cytokines like IL-10 and TGF-β.67,68 These modulations help to suppress excessive inflammation and promote immune tolerance. When co-cultured with MSCs, DCs exhibit impaired maturation from monocytes or CD34+ hematopoietic stem cells, as well as a reduced ability to produce pro-inflammatory cytokines.69 This is achieved through the downregulation of presentation molecules (HLA-DR and CD1a), co-stimulatory molecules (CD80 and CD86), and IL-12 in DCs.70,71 Additionally, MSCs inhibit DC differentiation by reducing the expression of major histocompatibility complex Class II, CD40, and CD86 co-stimulatory molecules, thereby decreasing T cell proliferation.72 MSCs also secrete IL-6, which leads to the upregulation of SOCS1 in DCs. This instructs DCs to acquire a tolerogenic phenotype, increasing their production of IL-10 and their ability to induce the differentiation of regulatory T cells (Tregs) and T helper 2 (Th2) cells. Aside from direct cell-to-cell contact, paracrine factors secreted by MSCs also play a role in modulating DC activity.73 MSC-derived extracellular vesicles (MSC-EV) impair the antigen uptake and maturation of immature DCs. This results in reduced expression of maturation and activation markers like CD83, CD38, and CD80, decreased secretion of pro-inflammatory cytokines IL-6 and IL-12p70, and an increase in the production of the anti-inflammatory cytokine TGF-β.74 Additionally, MSC-EV can interfere with DC antigen presentation by blocking their migration in response to CCL19(MIP-3 beta).75

Effects on natural killer (NK) cells. Natural killer cells (NK cells) are key effector cells of the innate immune system and possess the unique ability to eliminate virally infected, stressed, or cancerous cells.76 In addition to their role in eliminating damaged or dysfunctional cells, NK cells participate in regulating the balance between pro-inflammatory and anti-inflammatory responses. They achieve this by secreting cytokines and interacting with other immune cells, such as dendritic cells (DCs) and T cells.77 NK cells also play a role in regulating fibrotic responses and promoting angiogenesis in injured tissue. These functions of NK cells contribute to the overall processes of tissue repair and regeneration.

MSCs exert various effects on the physiological behavior of NK cells, including enhancing their cytotoxicity, inhibiting proliferation, regulating activation, modulating immunomodulatory functions, and influencing homing and migration.78,79 During the early stage of tissue healing, MSCs are stimulated to a pro-inflammatory phenotype (MSC1) and secrete anti-viral cytokines like INF-α and IFN-β.80 This upregulates the cytotoxic potential of NK cells. MSCs can also enhance the ability of IL-12/IL-18-stimulated NK cells to secrete IFN-γ, improving defense against infection at the injury site and influencing tissue regeneration.81 Co-culturing MSCs with NK cells increases the secretion of perforin and granzyme, which can induce target cell death. The regulation of NK cell proliferation by MSCs depends on the activating cytokines present.82 In the presence of IL-2, IL-12, IL-15, or IL-21 stimulation, MSCs significantly inhibit NK cell proliferation.83 MSCs can upregulate the expression of activating receptors on NK cells such as NKG2D and NKp46, while downregulating the expression of inhibitory receptors like killer cell immunoglobulin-like receptors (KIRs) and promoting their activation and cytotoxic functions.84 MSCs also produce chemokines like SDF-1 and MCP-1 to attract NK cells to specific tissues or sites of inflammation.85 Furthermore, MSCs can induce apoptosis of NK cells through both soluble factors and direct cell-to-cell contact.86 It is crucial to note that the interaction between MSCs and NK cells is a complex and dynamic process, with diverse effects depending on factors such as their ratio and the presence of specific stimulatory cytokines. Understanding these interactions is essential for harnessing the therapeutic potential of MSCs and NK cells in various immune-related conditions and diseases.

Effects on T cells. Cells of the adaptive immune system, particularly T cells, also play a role in mediating tissue repair by inhibiting inflammation through the modulation of N1 neutrophils, M1 macrophages, cytotoxic NK cells, and pro-inflammatory DCs.87 MSCs influence the physiological behavior of T cells by interacting with them through adhesion molecules, thereby impacting T cell proliferation, activation, and differentiation.88 For example, human placental mesenchymal stem cells (h-PMSCs) express high levels of cell adhesion molecules like programmed death ligand 1 (PD-L1) and PD-L2, which inhibit the cell cycle and block T cell proliferation.89 Interaction with MSCs leads to inhibited expression of cyclin D2 and upregulation of the cell cycle regulator p27(kip1), resulting in G1 phase arrest and suppressed T cell proliferation.90 However, when MSCs are removed and exogenous interleukin-2 (IL-2) is introduced, dormant T cells are reactivated and resume their immune response functions. MSCs can also inhibit the response of primitive and memory T cells to homologous antigens by upregulating intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1).91 Additionally, MSCs promote the differentiation of regulatory T cells (Tregs) through both direct cell contact and the secretion of paracrine factors like IL-10, PGE2, TGF-β, HLA-G5, and IL-10.92,93 MSCs enhance Treg differentiation by increasing IL-10 secretion and inhibiting the production of IFN-γ and IL-17.94,95
Effect on B cells. The precise mechanisms through which MSCs regulate B cells are not yet fully understood. However, several in vitro experiments have provided evidence of the inhibitory effects of MSCs on B cell proliferation, maturation, and antibody production.90 One study by Glennie et al. demonstrated that the co-culture of B cells with MSCs led to the arrest of B cell proliferation in the G0/G1 phase of the cell cycle. MSCs were also found to inhibit B cell maturation by secreting IL-1RA, which hampers the maturation process.48 Moreover, MSCs can secrete CCL2, which inhibits the activation of STAT3 and induces the expression of PAX5.96 This ultimately leads to the suppression of antibody production by B cells. MSCs can also downregulate the expression of chemokine receptors on the surface of B cells, thereby enhancing the immunomodulatory capacity of B cells.97 Additionally, studies have revealed that activated MSCs (A-MSCs) can increase the survival of quiescent B cells through contact-dependent mechanisms and promote B cell differentiation independently of T cells.98

2.2 The influence of immune response on exogenous MSCs fate

Traditionally, MSCs have been considered immune privileged due to their potent immunosuppressive capabilities and low expression of the major histocompatibility complex (MHC). However, recent studies on the immunogenic characteristics of MSCs have challenged this notion and instead propose that MSCs are immune evasive. Evidence suggests that the immune regulation properties of MSCs are dynamic, context-dependent, and sensitive to the surrounding milieu. MSCs can shift to a pro-inflammatory phenotype in a mildly inflammatory microenvironment or an anti-inflammatory phenotype in a strongly inflammatory microenvironment.99 Therefore, exogenous MSCs may not always exhibit immunosuppressive functions. Furthermore, the immune rejection of allogeneic MSCs is primarily driven by mismatches in the major histocompatibility complex (MHC) between the donor MSCs and the recipients. Among the numerous MHC molecules, MHC-I plays a pivotal role in determining the immunogenicity of MSCs. Even a small difference of just one amino acid between the MHC-I molecules of the donor and recipient can trigger recognition of non-self cells by the host's immune system and initiate a rejection response.100 Traditional in vitro studies have demonstrated that MSCs express low levels of surface MHC-I, which has been considered a major factor in their immune privilege.101 However, recent investigations have indicated that MHC-I expression is also sensitive to the environment and can be upregulated in the presence of inflammatory stimuli, such as IFN-γ.102 The level of alloimmune responses is closely linked to the expression of MHC-I on the surface of MSCs. Due to the upregulation of MHC expression and mismatch with host cells, immune cells such as macrophages, NK cells, and T cells are capable of recognizing surface antigens on allogeneic MSCs as non-self, triggering an immune response to eliminate them.103 Tracking studies have shown that most transplanted MSCs are cleared by the host immune system within days.104–107 For example, Toma et al. used intra-vital microscopy to track rat MSCs delivered intra-arterially and found that the surviving MSCs decreased to 14% of the initial number within 3 days post-delivery.108 Even in immunologically privileged areas like the brain or joints, immune rejection responses towards exogenous MSCs are still inevitable.109,110 Various immune cells participate in eliminating exogenous MSCs through mechanisms such as macrophage phagocytosis, NK cell cytotoxicity, and T cell-mediated cytotoxicity, Fig. 2 shows the specific removal methods.111,112 In a study on rhesus monkeys receiving intracranial injection of allogeneic MSCs, an increase in neutrophils, basophils, eosinophils, as well as specific subsets of NK cells and B cells containing detectable allo-specific antibodies was observed, indicating their participation in the allogeneic immune response mediated by exogenous MSCs.112 CD8+ cytotoxic T lymphocytes (CTLs) can recognize MHC-I molecules on allogeneic MSCs and kill them. CD4 + T lymphocytes can recognize MHC-II molecules on MSCs and transmit information to macrophages and B cells, recruiting them to participate in the immune rejection response.113 Activated NK cells can efficiently lyse allogeneic MSCs through receptors like NKp30, NKG2D, and DNAM-1, which are involved in inducing NK-mediated cytotoxicity against MSCs. This interaction not only leads to the lysis of MSCs, but also results in cytokine production by NK cells, further affecting the implantation environment.114 Allogeneic MSCs can also induce MHC-specific memory T lymphocytes, which can reduce the survival rate of subsequent injections of MSCs from the same source, contributing to immunological memory.115 Upon the second injection of the same allogeneic MSCs, the host produces a large number of antibodies and cytokines due to the previous immunological memory response, leading to the rapid elimination of the MSCs. Studies have shown that the clearance rate significantly increases after the second injection, with increased immune cells and chemokines produced in body fluids, as well as an upregulation of MHC expression, making the immune system more effective in targeting the MSCs.109
image file: d4tb00778f-f2.tif
Fig. 2 When allogeneic mesenchymal stem cells are injected into the host body, the original immune cells of the body reject the mesenchymal stem cells.

In transplantation procedures, tissue damage and the inflammatory response are inevitable. Inflammatory cells such as macrophages and neutrophils release pro-inflammatory cytokines including IFN-γ, TNF-α, ROS, and IL-17, creating an unfavorable environment for the survival of exogenous MSCs. Yi Liu et al. demonstrated that IFN-γ can inhibit the ability of exogenous MSCs to mediate bone repair by downregulating the Runx-2 pathway and enhancing TNF-α signaling in the stem cells.9 They also found that IFN-γ synergistically enhances TNF-α-induced apoptosis in MSCs. The use of systemic infusion of Foxp3+ regulatory T cells or local administration of anti-inflammatory agents to reduce the levels of IFN-γ and TNF-α can significantly improve the bone regeneration capacity of exogenous MSCs. Shi et al. showed that IL-17 or a combination of TNF-α and IFN-γ can activate NF-κB cascades in exogenous MSCs, leading to upregulated expression of the apoptotic pathway.116 Severe inflammation can cause an imbalance between ROS production and cellular antioxidant defense, leading to excessive ROS accumulation. High levels of ROS can damage cellular macromolecules in exogenous MSCs, including lipids, proteins, and DNA. Prolonged oxidative stress can trigger aging, apoptosis, or senescence of exogenous MSCs through the p53 pathway.117,118 Overall, the inflammatory response during transplantation procedures, characterized by the release of pro-inflammatory cytokines, ROS accumulation, and activation of apoptotic pathways, can negatively impact the survival and function of exogenous MSCs.119,120 Strategies aimed at reducing inflammation and oxidative stress may help improve the therapeutic efficacy of exogenous MSC-based therapies.

3. Biomaterial scaffold-based immune protection strategies for exogenous MSCs

Among the numerous challenges faced in achieving a higher survival rate of exogenous MSCs, the hostile environment induced by the immune response is a major hurdle that leads to rapid cell loss.121 Various strategies have been developed to protect exogenous MSCs from immune rejection and enhance their survival and integration post-transplantation. These strategies include preconditioning regimens, HLA matching, immune modulation therapy, tolerance induction techniques, and gene modification.122,123 They primarily aim to modulate the immunogenicity of exogenous MSCs. While the application of exogenous MSCs is typically combined with biomaterial scaffolds, researchers have recently started shifting their focus from MSCs to scaffolds to explore alternative immune-protective strategies. These strategies can be categorized into four main approaches: (1) Selecting appropriate scaffold matrices that can generate a favorable immune environment for MSC survival. (2) Optimizing the microstructure of the scaffold to spatially isolate the encapsulated MSCs from the host immune system. (3) Loading immunomodulatory agents onto the scaffold to suppress the bioactivity of the host immune system. (4) Co-encapsulating other immune cells with MSCs within the scaffold to modulate the immune response. By employing these scaffold-based strategies, researchers aim to create an environment that promotes the survival and function of exogenous MSCs while minimizing the detrimental effects of the immune response shown in Fig. 3. These approaches offer promising avenues for improving the efficacy of exogenous MSC-based therapies.20 Although various immune cell types played combined effects to determine the fate of exogenous MSCs, macrophages played the most important role during the whole process of tissue regeneration. Other immune cells, such as lymphocytes, natural killer cells, or neutrophils, only stayed for a short time period, while macrophages would take part in the whole regeneration process via sequentially secreting various cytokines. To modulate a favorable immune micro-environment for tissue regeneration, researchers mainly focused on regulating macrophage polarization by precisely controlling the micro-structure or biological function of biomaterial scaffolds. Therefore, we mainly focused on how to design biomaterial scaffolds to regulate the biological behavior of macrophages.
image file: d4tb00778f-f3.tif
Fig. 3 There are currently several forms and methods for protecting implanted stem cells, which mainly regulate the state of the immune microenvironment in which implanted stem cells are located through different physical encapsulation forms or the addition of immunosuppressive drugs. (The correct writing format has been modified in the figure).

3.1 Cross-talk between scaffolds and host immune system

After implantation of cell encapsulation systems, the immune system is inevitably activated due to the foreign nature of the scaffold materials, cell protrusion, and native responses associated with surgery.124 Selecting appropriate scaffold materials that can manipulate a favorable immune microenvironment is crucial for the survival of encapsulated MSCs. Biomaterials such as fibrin, collagen, gelatin, hyaluronic acid (HA), polycaprolactone (PCL), poly-(L-lactic acid) (PLA), and poly(lactic-co-glycolic acid) (PLGA) have been widely used to deliver MSCs in the form of hydrogels, sponges, or membranes. These biomaterials inadvertently elicit a foreign-body response, involving both the innate and adaptive immune responses. Macrophages play a pivotal role in the foreign-body response due to their high plasticity. Acute inflammation is triggered immediately after implantation, and macrophages are recruited and adhere to the scaffold. Initially, macrophages are stimulated towards a pro-inflammatory M1 phenotype, secreting cytokines and chemokines that are detrimental to the survival of exogenous MSCs. After 3–7 days, the macrophage phenotype switches to an anti-inflammatory M2 phenotype. M2 macrophages secrete anti-inflammatory cytokines to resolve inflammation or growth factors that promote MSC proliferation, differentiation, and extracellular matrix deposition. Both M1 and M2 macrophages are essential for tissue repair, and a lack of their proper activation results in frustrated phagocytosis. The sequence and control of macrophage M1-to-M2 polarization determine the fate of implants. Synthetic biomaterials generally exhibit poor biocompatibility, causing a severe acute inflammatory response, prolonging the persistence of the M1 phenotype and failing to switch to the M2 phenotype.125 This leads to an inability to resolve inflammation, resulting in a chronic inflammatory phase in the defect area. Additionally, the degraded products of synthetic biomaterials induce continuous chronic inflammation. Consequently, synthetic biomaterials are not ideal for delivering MSCs considering their therapeutic effects. Natural biomaterials such as collagen, gelatin, or HA are relatively innate and initiate a moderate foreign-body response due to their excellent biocompatibility, which is more beneficial for MSC survival. Some natural biomaterials possess inherent immunosuppressive effects. For example, HA hydrogels have been shown to promote the conversion of pro-inflammatory M1 macrophages to anti-inflammatory M2 macrophages. Researchers focus on improving the immunomodulatory function of natural biomaterials by tuning their chemical structures or components. Although collagen is widely considered as an ideal starting biomaterial for various medical devices due to its excellent biocompatibility and low cytotoxicity, animal-derived collagen has the potential risk of immunogenicity and inducing severe inflammatory responses.126 To address this issue, biosynthesis technology, combined with gene recombination, has been developed to produce recombinant humanized collagen. This recombinant collagen has been demonstrated to stimulate macrophage polarization toward the anti-inflammatory M2 phenotype and reduce pro-inflammatory cytokine secretion.127 Overall, selecting appropriate scaffold materials that promote a favorable immune microenvironment is essential for the survival and therapeutic effects of encapsulated MSCs. Natural biomaterials with immunomodulatory properties show promise in improving the outcomes of exogenous MSC-based therapies.128

3.2 Loading immunomodulatory agents

To enhance the immunomodulatory function of cell encapsulation systems, incorporating immunomodulatory agents into the system is a convenient strategy to create a favorable immune environment for MSC survival.129–132 Several types of immunomodulatory agents, including metal ions, anti-inflammatory drugs, and biological factors, have shown promise in controlling interactions between the cell-laden system and the host immune system. Metal ions such as zinc (Zn), magnesium (Mg), and strontium (Sr) have been found to enhance the expression of anti-inflammatory cytokines and maintain an anti-inflammatory environment.133 For example, Mg has been reported to reduce the production of pro-inflammatory cytokines from monocytes. Zn, as an essential trace element, can modulate the bioactivity of both innate and adaptive immune cells.134 Polymers with gold and silver ions combined with other elements can produce antimicrobial and reduce oxidative stress.135,136 These metal ions offer a means to regulate the immune response within the encapsulation system. In addition to metal ions, anti-inflammatory drugs can be incorporated into the cell encapsulation system to suppress the inflammatory response. For example, Shi et al. loaded indomethacin into an MSC delivery system, leading to additional improvements in the bone tissue regeneration capacity of the encapsulated MSCs by regulating the local microenvironment.16 It has also been shown that graphene oxide (GO) materials and hBMSC loading into photopolymerizable poly-D,L-lactic acid/polyethylene glycol (PDLLA) hydrogels promote cartilage formation by modulating the local microenvironment.137–139 Biological factors represent a more straightforward approach to regulate local immune responses and are often more effective in immunomodulation. Various biological factors, such as cytokines, genes, and extracellular materials, have been utilized to modulate inflammation. In hydrogel systems, anti-inflammatory cytokines like IL-4 and IL-10 have been loaded to manipulate the immune microenvironment. Hydrogels with dendritic polylysine and polysaccharide components or hydrogels containing newly synthesized protein peptide products140,141 have been studied to release cytokines that downregulate the PI3K/Akt pathway142 or inhibit NF-κB activation, and most of these hydrogels can promote macrophages to anti-inflammatory M2 polarization and reduce the production of pro-inflammatory cytokines. Genes and extracellular vesicles have also shown potential for immune modulation. However, a challenge for these composite systems is to adhere to the immunological principles during tissue regeneration. In MSC-based tissue regeneration, the process is regulated by both implanted MSCs and resident endogenous MSCs, under the influence of the immune system. A moderate inflammatory response is essential for the recruitment, proliferation, and differentiation of endogenous MSCs. It is important to note that immunomodulatory agents primarily target inhibiting the inflammatory response. Uncontrolled release of these agents can over-inhibit the bioactivity of the host immune system or disrupt its sequential function, ultimately hindering endogenous tissue regeneration.143 Therefore, achieving a controlled release profile of immunomodulatory agents, which regulates a moderate immune response rather than completely inhibiting inflammation, is crucial to facilitate high-quality tissue regeneration. Careful consideration of the release kinetics of these agents will be vital for achieving optimal outcomes in MSC-based tissue engineering approaches.144

To regulate a favorable immune response following immunological principles during tissue regeneration, various strategies have been explored in the design of advanced immunomodulatory biomaterials, including sustainable release patterns, smart release patterns, and biphasic drug delivery systems.145–147 These strategies can be applied to design immunomodulatory agents loaded in cell encapsulation systems. One approach is the development of sustainable release patterns. Nano-carriers, such as mesoporous silica or halloysite, can be used as drug carriers to physically retard the diffusion of drugs and avoid the side effects of initial burst release. This sustained release pattern helps to prevent over-inhibition of the initial inflammatory response.148 By controlling the release rate, sustained release patterns provide a continuous and moderate immunomodulatory effect. Another approach is the development of smart release patterns, also known as self-regulated systems. In this approach, drug release is triggered by abnormal biological signals and subsequently influences those signals to generate feedback. For example, in an inflammatory environment, acidic pH or an over-expressed esterase can be selected as triggers and ester groups can be designed as sensitive groups. A modified drug, such as tannic acid–indomethacin (TA–IND), can be synthesized via esterification reactions. This modified drug is slowly released in a normal biological environment due to the spontaneous hydrolysis of the ester groups. However, in response to inflammation, the drug release is accelerated, subsequently inhibiting the inflammatory response.149 These smart release patterns allow for precise control of the inflammation to a moderate level and have shown superior tissue regeneration performance compared to direct drug-loaded systems. Biphasic drug delivery systems have also been developed to stimulate the proper timing of M1 or M2 macrophage activation, which is essential for the normal tissue repair process. These systems aim to mimic the sequential function of distinct macrophage phenotypes, thereby determining the fate of implants.150 In biphasic drug delivery systems, an initial fast release of recruitment or stimulating agents is needed to promote M1 macrophage infiltration and polarization. In the second phase, M2-promoting stimuli are delivered to induce phenotype switching. This enables the controlled and timely transition from M1 to M2 macrophage activation. For example, multidomain self-assembling peptide hydrogels have been designed to control the sequential release of monocyte chemoattractant protein-1 (MCP-1) and interleukin-4 (IL-4).151 MCP-1 is released initially to recruit monocytes to the implant environment and bolster resident M1 activity. Then, the subsequent release of IL-4 polarizes macrophages to an M2a phenotype. This biphasic drug delivery approach allows for more accurate regulation of the immune response during tissue regeneration. By employing sustainable release patterns, smart release patterns, and biphasic drug delivery systems, it is possible to design immunomodulatory agents loaded in cell encapsulation systems that optimize the immune response and promote successful tissue regeneration.152

3.3 Cell encapsulation systems

Cell encapsulation within semi-permeable hydrogels represents a local immuno-isolation strategy for cell-based therapies without the need for systemic immunosuppression.153 This strategy was primordially designed to protect and mask the pancreatic islet cells from the immune system for the treatment of diabetes mellitus.20 The core technology for the design of these systems is the semi-permeable function, maximizing the diffusion of essential nutrient molecules for cell survival while retarding the invasion of immune cells and detrimental cytokines into the matrix. Controlling the crosslinking density of the cell encapsulation matrix is one pathway to adjust its mass transition. Alginate systems provide the simplest example for the case of controlling crosslinking density by controlling the concentration of calcium or crosslinking time, or replacing calcium with barium, or selecting alginates richer in guluronic acid units. However, crosslinking control will also result in matrices with distinct stiffness that will play an important role in cell behavior, namely on the ability of stem cells to differentiate into specific lineages.154,155 To protect human bone marrow MSCs against insult from the host immune system, Shi et al. constructed a porous alginate scaffold with an average pore size of 600 nm, making it a selective barrier for cytokines and/or T-lymphocytes. To optimize the permeability of the hydrogel based on diffusion rate analysis, they decided to utilize alginate hydrogel with an intermediate stiffness of 22 Kpa. They found that the designed alginate cell encapsulation system can act as a physical barrier to partially hinder the infiltration of pro-inflammatory cytokines and T-lymphocytes, thus reducing apoptosis of encapsulated MSCs.16 Similarly, alginic acid saline gel, with smaller pores and lower porosity but higher elasticity, can significantly inhibit the infiltration of proinflammatory cytokines and the activation of NF-κB signals. Furthermore, MSCs encapsulated in hydrogels with high elasticity demonstrated lower expression levels of NF-κB-p65 and Cox-2 in vivo. The mechanical properties and microstructure of the microenvironment that encapsulates MSCs have a profound impact on the fate of the loaded stem cells.156 By regulating the characteristics and properties of biomaterials, including their degradation kinetics, molecular compatibility, and porosity, it becomes possible to achieve spatiotemporal control of extracellular signals.157,158 These features are crucial in designing biomaterials that can better support the function and survival of implanted stem cells.

At present, there have been more and more studies on cell encapsulation systems. Most of the encapsulated cells are mesenchymal stem cells, there are also other cells, as listed in Table 1, most of the encapsulation systems use self-designed hydrogels or add newly synthesized drugs to some classical hydrogels, by promoting the differentiation of stem cells, regulating NF-κB, PI3K/Akt or other apoptotic pathways to reduce the removal of immune cells and the damage of inflammatory factors by stem cells.132,142,159 Finally, tissue repair and regeneration functions can be completed by prolonging the survival time of stem cells, regulating the local immune environment, and promoting blood vessels and collagen production. Like what a composite scaffold system (RF-pGel-MS), which consisted of an outer ROS filter (RF) and an inner porous GelMA hydrogel (pGel) harbored with MSC spheroids (MSs), was designed for SCI repair. Specifically, RF rapidly scavenged ROS, protecting the MS from peroxidation damage in the acute phase.160

Table 1 At present, there have been more and more studies on cell encapsulation systems, most of the encapsulated cells are mesenchymal stem cells, and there are also other cells, as listed here
  Cell species Composition of the stent structure The main method of regulation Animal models Bibliography
Loading Immunomodulatory agents MSCs Mg Activating PI3K)-AKT Cartilage defect(Rb) 133
MSCs AgGNR(IL-4)-loaded PgelDex Anti-inflammatory — 135
Anti-bacterial
BASCs Au@Pt nanoparticles EliminateROS MI rat 136
Reduce the inflammatory factors
h-BMSC (PDLLA) hydrogel and GO Higher gene expression of the cartilage matrix, aggrecan and col- II and produced more cartilage matrix — 137–139
hADMSCs PGmatrix-a new peptide- Secreted more immune-responsive proteins Diabetic mice wound skin model 140
MSCs Interferon γ (IFN-γ) loaded heparin-coated beads are incorporated Enhanced Gal-9 suppressed human T cells — 145 and 146
Co-encapsulating other immune cells MSC Alginate hydrogel Reduce MSC viability through the CASPASE-3 and CASPASE-8 associated proapoptotic cascade WT animal model 132 and 156
m-MSCs Host–guest-Ca-Neu hydrogel Triggered-PI3K/Akt to promote neuronal regeneration after SCI, establishes an anti-inflammatory microenvironment SCI-rat 142
MSCs Hybrid myoglobin:peptide hydrogel Inhibit ferroptosis by improving vascular function and regulating iron metabolism — 147
DPSCs TPA@LAPONITE® hydrogel Increase in injected MSC half-life by more than an order of magnitude — 157
m-MSCs Cell cluster cross-linking with poly-lysine Facilitate the cartilage-specific genes expression and extracellular matrix secretion Allogeneic BM transplantation stroke injured brain SCI 158
(PB-MSCs MSC spheroids (MSs) Polyethylene glycol (PEG) and kartogenin (KGN)-conjugated outer ROS filter (RF) and inner porous GelMA hydrogel (p-Gel) harbored with MSs Scavenged ROS, protecting the MS from peroxidation damage in the acute phase — 160

Of note, considering the application of tissue regeneration, such immune isolation systems are completely distinct from the classical long-term immunoprotective feature of the primordial cell encapsulation systems. In order to promote proper tissue regeneration and tissue integration, it is desirable to occur the degradation of the encapsulation matrix, which will lead to its loss of physical barrier function towards the host immune system. The immunoisolation cell encapsulation systems can find great applicability during the initial acute inflammatory phase; it can isolate the exogenous MSCs from the harsh acute inflammatory environment, thus prolonging their survival time.

4. Conclusions

Over the past decades, exogenous MSC-based regeneration strategies have shown great promise for tissue regeneration. However, the therapeutic efficacy is still limited due to the poor survival rate of transplanted MSCs, primarily caused by immune rejection. To address this challenge, various immune protection strategies have been established to optimize MSC-based tissue regeneration and have demonstrated enormous potential. One approach is to modulate the immune microenvironment to create conditions that are beneficial for MSC survival. Another approach involves physically isolating exogenous MSCs from the host immune system. While significant progress has been made, there are still several important areas that require further exploration. First, more studies are needed to understand the immune microenvironmental modulation of MSC-based tissue regeneration and the underlying molecular mechanisms involved. This knowledge will help identify key molecules and signaling pathways that contribute to MSC-based therapies. Second, novel techniques such as 3D bio-printing can be employed to precisely design the nano-topography or microstructure of MSC encapsulation systems. These physical signals can modulate the immune microenvironment and promote the survival of MSCs. Third, scaffold biomaterials can be modified to regulate the interaction between the scaffold and the host immune system, creating a favorable immune microenvironment for MSC survival. Finally, co-loading immunomodulatory drugs and MSCs in cell encapsulation systems can enable precise control of the drug release profile. This controlled release can help manipulate the immune response in line with the principles of tissue regeneration. In summary, by understanding the effects of the immune microenvironment on MSCs, we can gain insight into the pathogenesis and therapeutics of tissue regeneration. This understanding will promote the development of optimized MSC-based strategies for regenerative medicine. Continued research and advancements in this field will contribute to unlocking the full potential of MSC-based therapies for tissue regeneration.

Conflicts of interest

The authors declared no potential conflicts of interest.

Acknowledgements

The authors expressed gratitude to their representative institutes and universities for providing access to the literature, and this work was supported by the National Key Research and Development Program of China (2021YFA1100603) and the Fundamental Research Funds for the Central Universities (SCU2023D014).

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