Mesenchymal Stem Cell Immunomodulation: Mechanisms and Therapeutic Potential

doi:10.1016/j.tips.2020.06.009

Trends in Pharmacological Sciences

Volume 41, Issue 9, September 2020, Pages 653-664

https://doi.org/10.1016/j.tips.2020.06.009 Get rights and content

Highlights

MSCs are multipotent cells that are emerging as the most promising means of allogeneic cell therapy.
MSCs participate in both innate and adaptive immunity, and their immunomodulatory functions are exerted mainly via interactions with immune cells through cell-to-cell contact and paracrine activity.
Engineering MSCs to express specific immunomodulatory agents contributes to MSC capacity and pluripotency, and also enables them to deliver large doses of cancer-targeting biologics with a single dose.
MSC administration has shown potential efficacy in the treatment of several diseases that resist standard treatment. However, there are some challenges in efficiently translating MSC-based therapeutics into the clinic.
Efficient homing and migration of MSCs to the target tissue will be essential for the future development of MSC-based therapies.

Mesenchymal stem/stromal cells (MSCs) are multipotent cells that are emerging as the most promising means of allogeneic cell therapy. MSCs have inherent immunomodulatory characteristics, trophic activity, high in vitro self-renewal ability, and can be readily engineered to enhance their immunomodulatory functions. MSCs affect the functions of most immune effector cells via direct contact with immune cells and local microenvironmental factors. Previous studies have confirmed that the immunomodulatory effects of MSCs are mainly communicated via MSC-secreted cytokines; however, apoptotic and metabolically inactivated MSCs have more recently been shown to possess immunomodulatory potential, in which regulatory T cells and monocytes play a key role. We review the immunomodulatory aspects of naïve and engineered MSCs, and discuss strategies for increasing the potential of successfully using MSCs in clinical settings.

Section snippets

Mesenchymal Stem Cells

MSCs are pluripotent T cells that have self-renewing, differentiation, and immunomodulatory properties. Their two most attractive features are plasticity (see Glossary) and tropism. They are distinguished from other cell types by the expression of cell-surface markers including CD73, CD90, and CD105, and by the lack of expression of CD45, CD34, CD14, CD19, CD11b, and human leukocyte antigen DR isotype (HLA-DR) [1], and play a central role in tissue repair in addition to their antitumorigenic,

Immunomodulation by MSCs

MSCs have recently been shown to possess immunomodulatory potential in which interactions with regulatory T cells (Tregs) and monocytes play a key role [2,10]. Several studies have suggested that A-MSCs exert more potent immunomodulatory effects than BM-MSCs, implying that A-MSCs are a better alternative for immunomodulatory therapy [11]. UC-MSCs, on the other hand, have been suggested to show minimal risk of initiating an allogeneic immune response when administered in vivo. This, as well as

Immunomodulatory Actions through Cell-to-Cell Contacts

MSCs participate in both innate immunity and adaptive immunity, and their immunomodulatory functions are exerted mainly via interactions with immune cells through cell-to-cell contact and paracrine activity involving T cells, B cells, natural killer (NK) cells, macrophages, monocytes, dendritic cells (DCs), and neutrophils [12] (Figure 1).

Immunomodulatory Actions through Paracrine Activity

Importantly, MSCs also exert their immunomodulatory properties by secreting multifunctional molecules via paracrine mechanisms [12] (Figure 1). This secretome is a diverse repertoire of multifaceted cytokines, growth factors, and chemokines, which combine to modulate the function of immune and cancer cells. These include transforming growth factor-β1 (TGF-β1), tumor necrosis factor-α (TNF-α), PGE2, IFN-γ, hepatocyte growth factor (HGF), fibroblast growth factor (FGF), indoleamine-pyrrole

Preconditioning MSCs To Increase Their Immunomodulatory Functions and Therapeutic Efficacy

Preconditioning of MSCs is known to influence their therapeutic efficacy, and modification with diverse factors and a variety of conditions have therefore been explored to manipulate the secretory profiles and enhance the therapeutic efficacy of MSCs [53]. Preconditioning MSCs with hypoxia, oxidative stress, heat shock, starvation, or inflammatory biological agents has potential to increase their survival and potency [53]. The main methods of preconditioning are hypoxia and priming with

Engineering MSCs To Increase Their Immunomodulatory Functions and Therapeutic Efficacy

MSCs have an intrinsic ability to evade the immune response temporarily. In the context of using MSCs for targeted therapy, they are mainly considered as gene delivery vehicles for immunomodulatory molecules such as IFNs and ILs, or are engineered to deliver oncolytic viruses (OVs) (Figure 2A). Engineering MSCs to express specific immunomodulatory agents contribute to their immunomodulatory capacity and pluripotency, and also enables them to deliver large doses of cancer-targeting biologics

MSC-Mediated Immunomodulation in Clinical Studies and Trials

MSC infusion has shown potential efficacy in the treatment of several diseases that resist standard treatment. For example, in a Phase I/II clinical trial (EuDRA CTⁱ: 2012-003741-15) involving autologous tumor-specific herpes simplex virus thymidine kinase (HSV-TK), MSCs demonstrated favorable safety and tolerability in patients with gastrointestinal tumors: the median time to progression was 1.8 months, and median overall survival was 15.6 months (Table 2) [82,83]. However, the study was

Promising Preclinical Studies That Have Potential To Increase the Efficacy of Future MSC Trials

Apart from improving immunomodulatory capacity of MSCs (Figure 2A), there are several approaches to improve MSC migration or homing mechanisms (Figure 2B). Recent studies have shown that MSC homing is driven by SDF-1-stimulated endothelial cell production of platelet-derived growth factor (PDGF) via activation of PDGF receptor A (PDGFRA)/PI3K/Akt, PDGFRA/MAPK/Grb2, and PDGFRA/JAK2/STAT signaling [91]. In addition, FGF21 also influences the homing ability of MSCs to injury sites [92], and

Concluding Remarks and Future Perspectives

MSCs have emerged as a promising therapeutic strategy because of their tropism for other cell types as well as their immunomodulatory functions. The immunomodulatory ability of MSCs is regulated by different inflammatory cytokines, and the interaction between immune cells and MSCs could contribute to regeneration as well as to the progression of different inflammatory diseases. The main mechanisms involved in MSC immunomodulation are cell-to-cell contact and paracrine activity primed by

Acknowledgments

This work was supported by National Institutes of Health grant R01-NS107857 and Department of Defence grant CA180698 to K.S.

Disclaimer Statement

K.S. owns equity in and is a member of the Board of D irectors of AMASA Therapeutics, a company developing stem cell-based therapies for cancer; his interests were reviewed and are managed by Brigham and Women’s Hospital and Partners HealthCare in accordance with their conflict of interest policies. The other authors declare that they have no competing interests.

Glossary

Adaptive immunity: a subset of the immune system that is activated by exposure to pathogens and acts on the threat using an immunological memory to enhance its effect. Cells of the adaptive immune system include B and T cells.
Allogeneic: tissues or cells from individuals of the same species, but which are genetically dissimilar and hence immunologically incompatible.
Dendritic cells (DCs): antigen-presenting cells in the mammalian immune system. DCs act as messengers between the innate and the

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Trends in Pharmacological Sciences

ReviewMesenchymal Stem Cell Immunomodulation: Mechanisms and Therapeutic Potential

Highlights

Section snippets

Mesenchymal Stem Cells

Immunomodulation by MSCs

Immunomodulatory Actions through Cell-to-Cell Contacts

Immunomodulatory Actions through Paracrine Activity

Preconditioning MSCs To Increase Their Immunomodulatory Functions and Therapeutic Efficacy

Engineering MSCs To Increase Their Immunomodulatory Functions and Therapeutic Efficacy

MSC-Mediated Immunomodulation in Clinical Studies and Trials

Promising Preclinical Studies That Have Potential To Increase the Efficacy of Future MSC Trials

Concluding Remarks and Future Perspectives

Acknowledgments

Disclaimer Statement

Glossary

Cytotherapy

Cell Stem Cell

Intl. J. Biochem. Cell Biol.

Cancer Lett.

Adv. Drug Deliv. Rev.

J. Clin. Med.

Blood

Blood

J. Hematol. Oncol.

The multifaceted role of mesenchymal stem cells in cancer

Semin. Cancer Biol.

Comparison of molecular profiles of human mesenchymal stem cells derived from bone marrow, umbilical cord blood, placenta and adipose tissue

Intl. J. Molec. Med.

Comparison of immunological characteristics of mesenchymal stem cells from the periodontal ligament, umbilical cord, and adipose tissue

Stem Cells Int.

Stem cell-based therapies for tumors in the brain: are we there yet?

Neuro-oncology

Immunomodulation by mesenchymal stem cells (MSCs): mechanisms of action of living, apoptotic, and dead MSCs

Front. Immunol.

Multipotent stromal cells skew monocytes towards an anti-inflammatory interleukin-10-producing phenotype by production of interleukin-6

Haematologica

Inflammatory cytokine-induced intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in mesenchymal stem cells are critical for immunosuppression

J. Immunol.

Immunological modulation following bone marrow-derived mesenchymal stromal cells and Th17 lymphocyte co-cultures

Inflamm. Res.

Notch1 modulates mesenchymal stem cells mediated regulatory T-cell induction

Eur. J. Immunol.

Human multipotent mesenchymal stromal cells use galectin-1 to inhibit immune effector cells

Blood

Toll-like receptors 3 and 4 are expressed by human bone marrow-derived mesenchymal stem cells and can inhibit their T-cell modulatory activity by impairing Notch signaling

Stem Cells

Expression and biological function of programmed death ligands in human placenta mesenchymal stem cells

Cell Biol. Int.

CD90low MSCs modulate intratumoral immunity to confer antitumor activity in a mouse model of ovarian cancer

Oncotarget

Cell-cell contact with proinflammatory macrophages enhances the immunotherapeutic effect of mesenchymal stem cells in two abortion models

Cell. Mol. Immunol.

A critical role of IFNγ in priming MSC-mediated suppression of T cell proliferation through up-regulation of B7-H1

Cell Res.

Human adipose tissue-derived mesenchymal stem cells abrogate plasmablast formation and induce regulatory B cells independently of T helper cells

Stem Cells

Mesenchymal stromal cells protect against caspase 3-mediated apoptosis of CD19+ peripheral B cells through contact-dependent upregulation of VEGF

Stem Cells Dev.

The effect of mesenchymal stem cells on the viability, proliferation and differentiation of B-lymphocytes

Haematologica

Immunomodulation by therapeutic mesenchymal stromal cells (MSC) is triggered through phagocytosis of MSC by monocytic cells

Stem Cells

Differential immunomodulatory effects of human bone marrow-derived mesenchymal stromal cells on natural killer cells

Stem Cells Dev.

Adipose stromal cells mediated switching of the pro-inflammatory profile of M1-like macrophages is facilitated by PGE2: in vitro evaluation

Osteoarthr. Cartil.

Suppression of neutrophil-mediated tissue damage – a novel skill of mesenchymal stem cells

Stem Cells

Interactions between mesenchymal stem cells and the immune system

Cell. Mol. Life Sci.

Adipose tissue derived stem cells secretome: soluble factors and their roles in regenerative medicine

Curr. Stem Cell Res. Ther.

Mesenchymal stromal cell secretome: influencing therapeutic potential by cellular pre-conditioning

Front. Immunol.

Interaction between mesenchymal stromal cell-derived extracellular vesicles and immune cells by distinct protein content

J. Cell. Physiol.

A review of therapeutic effects of mesenchymal stem cell secretions and induction of secretory modification by different culture methods

J. Transl. Med.

Mesenchymal stem cells inhibit human Th17 cell differentiation and function and induce a T regulatory cell phenotype

Review
Mesenchymal Stem Cell Immunomodulation: Mechanisms and Therapeutic Potential

Mesenchymal stromal cells protect against caspase 3-mediated apoptosis of CD19⁺ peripheral B cells through contact-dependent upregulation of VEGF