Immunomodulatory mechanisms of MSCs in acute GvHD

Acute graft-versus-host disease (aGvHD) is a significant immune-mediated complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), with only ~60% of patients experiencing a response to first-line treatment with high-dose corticosteroids.^1–3 Ruxolitinib is the consensus second-line treatment for steroid-refractory aGvHD (SR-aGvHD); however, responses are not sustained in a substantial proportion of patients, highlighting the need for alternative treatment approaches.^1–4  

Mesenchymal stromal cells (MSCs) have been evaluated as a potential treatment for SR-aGvHD due to their immunomodulatory properties.⁵ Remestemcel-L, an MSC product, was approved by the U.S. Food and Drug Administration (FDA) in December 2024 for the treatment of pediatric patients (aged ≥2 months) with SR-aGvHD.⁶ As MSCs lack human leukocyte antigen class II expression, they can be administered as an allogeneic therapy without donor−recipient matching.⁷ Although the precise mechanisms underlying the effects of MSCs in aGvHD remain incompletely understood, evidence suggests that their therapeutic activity is mediated by multiple interconnected pathways involving soluble factors, extracellular vesicles (EVs), and modulation of immune-cell function.^7,8 In this article, we explore the proposed immunomodulatory mechanisms underlying the therapeutic effects of MSCs in aGvHD. 

Proposed mechanisms of MSC-mediated immunomodulation in aGvHD  

MSCs promote an immunosuppressive and immunoregulatory environment via several potentially overlapping mechanisms (Figure 1).⁷ Although no single dominant mechanism has been conclusively established in patients with aGvHD, proposed mechanisms include:⁹ 

 1) EV-mediated transfer of bioactive molecules. MSCs release EVs, including exosomes and microvesicles, that carry RNA and other bioactive molecules capable of influencing target cell function.⁷ Although the mechanisms underlying EV-mediated immunomodulation remain under investigation, one proposed process involves the shuttling of MSC-derived interleukin-10 (IL-10) messenger RNA to recipient cells that lack this transcript, enabling them to produce this anti-inflammatory cytokine.^9–11  

2) Paracrine signaling, including the secretion of proteins, peptides, and hormones. MSCs secrete a range of soluble factors that have been proposed to mediate immunosuppressive activity, including transforming growth factor-β1, prostaglandin E2 (PGE2), hepatocyte growth factor (HGF), indoleamine 2,3-dioxygenase (IDO), nitric oxide, and IL-10.^7,8 Inflammatory cytokines, such as interferon-γ and tumor necrosis factor-α, can stimulate MSCs to further increase IDO production, which in turn leads to suppression of allogeneic T-cell proliferation.^7,8 As exposure to inflammatory signals supports the immunosuppressive function of MSCs, their administration earlier in aGvHD, when pro-inflammatory signals may be more pronounced, could enhance their therapeutic activity.⁹ 

3) Organelle transfer. MSCs can transfer mitochondria to target cells through direct cell-to-cell connections known as tunneling nanotubes.⁷ In experimental studies, mitochondrial transfer from MSCs to T cells has been associated with induction of regulatory T-cell differentiation and reduced inflammatory activity.¹² As T cells play a central role in the pathogenesis of aGvHD, this mechanism may help limit T-cell-mediated inflammation and tissue damage.¹³ 

4) Apoptosis of MSCs. MSCs undergoing apoptosis in vivo may exert immunomodulatory effects through the production and release of apoptotic EVs and interactions with recipient phagocytes.⁷ For example, apoptotic MSCs have been reported to induce IDO production in recipient phagocytes, thereby promoting an immunosuppressive environment.¹⁴  

Collectively, these mechanisms may influence the activity and function of multiple immune cell populations involved in aGvHD (Figure 2).^7,8,15 These effects may include suppression of B- and T-cell proliferation, generation and induction of regulatory T cells, and inhibition of natural killer cell activation and cytotoxicity. MSCs may also impair dendritic cell maturation and activation via secretion of PGE2, thereby reducing antigen presentation and their capacity to activate effector T cells.^8,15 Together, these effects may promote a more tolerogenic environment and limit the alloreactive immune responses that drive tissue injury in aGvHD.¹⁶  

Current evidence suggests that MSCs exert variable immunomodulatory effects on the same types of immune cells depending on the local microenvironment or disease status.⁸ For example, MSC treatment is associated with a reduction in the relative proportion of T helper 1 (Th1) cells in patients with aGvHD;¹⁷ however, bone marrow-derived MSCs can also promote a shift from Th2 to Th1 responses in airway allergic inflammatory diseases.^18–20 These findings suggest that MSCs can switch their effects to protect the body from disease in different situations.⁸ 

Tissue-protective and reparative effects of MSCs 

In addition to their immunomodulatory effects, MSCs have been shown to limit tissue damage and stimulate tissue repair.⁷ It was originally hypothesized that, upon administration, MSCs would migrate to sites of injury, engraft, and differentiate into functional cells to replace damaged tissue. However, emerging evidence suggests that MSC-mediated tissue repair may occur primarily through alternative mechanisms, particularly the paracrine secretion of growth factors, cytokines, and other bioactive mediators that influence the function of endogenous recipient cells. These factors, including vascular endothelial growth factor, platelet-derived growth factor, and HGF, can contribute to tissue rescue and repair, although their specific protective and reparative effects in aGvHD are yet to be fully characterized.^7,21 

Future directions and research gaps 

While several studies have reported encouraging outcomes with MSC therapy in aGvHD, others have shown limited or inconsistent efficacy. This variability may reflect differences in MSC source, inter-donor availability, manufacturing processes, and clinical trial design.^7,22 Tomostrocel is a standardized, pooled bone marrow-derived MSC product designed to minimize inter-donor variability in MSC products.²² Results from a real-world analysis of tomostrocel for steroid- or treatment-refractory pediatric aGvHD have recently been summarized on the GvHD Hub.²² Further clinical evaluation is needed to determine whether MSC product standardization translates into more consistent treatment outcomes. 

Defining the patient subgroups most likely to benefit from MSC therapy remains an important research need. Some studies have reported differences in MSC treatment response according to aGvHD severity and organ involvement, with improved response rates observed in patients with higher-grade disease and those with skin involvement; however, further evaluation is needed to validate these findings.^23,24 Moreover, the identification of biomarkers that can differentiate MSC responders from non-responders may also help refine patient selection.²⁴ 

In practice, MSCs are often co-administered with other immunosuppressive therapies, but the effects of these combinations on MSC therapeutic activity remain unclear.^9,25 Ongoing and planned US-based trials, including a phase III trial combining MSCs with ruxolitinib as second-line therapy for SR-aGvHD (NCT07568535), may provide further insights into the role of combination therapy in this setting.²⁶ 

Conclusion 

In summary, MSCs are believed to exert broad immunomodulatory effects in aGvHD through multiple interconnected mechanisms, including paracrine signaling, EV-mediated transfer of RNA and other molecules, mitochondrial transfer, and apoptosis, which may collectively influence immune-cell activity and help limit tissue injury.^7,8 Despite these advances in understanding, further research is needed to better characterize the mechanisms underlying MSC activity and establish its optimal clinical use in SR-aGvHD. 

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