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Mesenchymal stem cells in health and disease

Key Points

  • Bone-marrow-derived multipotent progenitor stromal cells — or mesenchymal stem cells (MSCs) — are the common predecessors of cells of the mesenchymal lineage, such as bone, cartilage and fat cells. They can also differentiate into cells from unrelated germline lineages (a process known as transdifferentiation).

  • Bone-marrow-derived stromal cells are the functional components of the haematopoietic stem cell (HSC) niche that support HSC homeostasis and they have anti-proliferative features that are in common with physiological stromal niches.

  • MSCs regulate many effector functions of innate immune cells, such as antigen presentation by dendritic cells (DCs), natural killer (NK)-cell cytotoxicity and the activation of neutrophils. However, activated NK cells can also kill MSCs.

  • MSCs inhibit T-cell proliferation through the induction of cell-division arrest, which is enhanced by interferon-γ released by activated T cells. MSCs also impair B-cell functions, such as antibody production.

  • After in vivo intravenous administration, MSCs can induce T-cell peripheral tolerance, home to inflamed tissues and exert a potent tissue-protective effect through the release of anti-inflammatory, anti-apoptotic and trophic molecules. In vivo studies indicate that the therapeutic effect of MSCs occurring through cell replacement is limited.

  • Clinical exploitation of in vitro-cultured MSCs has been safely carried out in some human conditions, which indicates that MSCs might be a new strategy for the treatment of immune-mediated diseases.

Abstract

Mesenchymal stem cells (MSCs) are a heterogeneous subset of stromal stem cells that can be isolated from many adult tissues. They can differentiate into cells of the mesodermal lineage, such as adipocytes, osteocytes and chondrocytes, as well as cells of other embryonic lineages. MSCs can interact with cells of both the innate and adaptive immune systems, leading to the modulation of several effector functions. After in vivo administration, MSCs induce peripheral tolerance and migrate to injured tissues, where they can inhibit the release of pro-inflammatory cytokines and promote the survival of damaged cells. This Review discusses the targets and mechanisms of MSC-mediated immunomodulation and the possible translation of MSCs to new therapeutic approaches.

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Figure 1: The multipotentiality of MSCs.
Figure 2: Stromal cells in the haematopoietic-stem-cell niche.
Figure 3: Possible mechanisms of the interactions between MSCs and cells of the innate and adaptive immune systems.
Figure 4: The bystander effects of MSCs on neural cells.

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Acknowledgements

Some of the studies reported in this manuscript were supported by grants to A.U., L.M. and V.P. from the Fondazione Italiana Sclerosi Multipla (FISM), the Istituto Superiore di Sanità (ISS), the Italian Ministry of Health (Ricerca Finalizzata and Programma Integrato Ricerca Oncologica), the Italian Ministry of the University and Scientific Research (MIUR), the European Union FP6, the Fondazione Compagnia di San Paolo, Torino, Italy, the Fondazione CARIGE and the Fondazione CARIPLO.

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Glossary

Stromal cells

Cells of non-lymphoid origin that form the framework of each organ. By expressing various molecules, these cells can support the adhesion, proliferation and survival of distinct cell subsets.

Mesenchymal tissues

These are embryonic tissues of mesodermal origin, consisting of loosely packed, unspecialized cells set in a gelatinous ground substance, from which connective tissue, bone, cartilage and the circulatory and lymphatic systems develop.

Transdifferentiation

The ability of a non-stem cell to transform into a different type of cell lineage, or when an already partially differentiated stem cell transforms into a different cell lineage or type.

Stem cells

A subset of cells that has a self-renewing capacity and under appropriate conditions can give rise to several mature cell lineages.

Mesodermal lineage

In animals with three tissue layers, the mesoderm is the middle layer of tissue, between the ectoderm and the endoderm. In vertebrates, the mesoderm forms the skeleton, muscles, heart, spleen and many other internal organs.

HSC niche

The microenvironment inside the trabecular bone cavity, which is composed of a specialized population of cells that has an essential role in regulating the self-renewal and differentiation of haematopoietic stem cells (HSCs).

Haematopoiesis

The commitment and differentiation processes that lead from a haematopoietic stem cell to the production of mature cells of all blood lineages — erythrocytes, myeloid cells (macrophages, mast cells, neutrophils and eosinophils), B and T cells, and natural killer cells.

Sinusoids

Blood-filled spaces that lack the anatomy of a capillary. Sinusoids generally contain slow-flowing blood, which facilitates cellular interactions. Such vessels are found in the bone marrow and in the liver.

Respiratory burst

A large increase in oxygen consumption and the generation of reactive oxygen species that accompanies the exposure of neutrophils to microorganisms and/or inflammatory mediators.

Activation-induced cell death

A process by which activated, T-cell-receptor-restimulated T cells undergo cell death after engagement of cell-death receptors, such as CD95 or the tumour-necrosis factor receptor, or after exposure to reactive oxygen species.

HLA-G

A non-classical MHC class Ib molecule that is involved in the establishment of immune tolerance at the maternal–fetal interface, the major soluble isoforms of which are HLA-G1 and HLA-G5.

Notch signalling

A signalling system comprising highly conserved transmembrane receptors that regulate cell-fate choice in the development of many cell lineages, and so are crucial for the regulation of embryonic differentiation and development.

Antibody-secreting cells

A term that denotes both proliferating plasmablasts and non-proliferating plasma cells. The term is used when both cell types might be present.

Multiple sclerosis

A chronic inflammatory and demyelinating disease of the central nervous system. Multiple sclerosis involves an autoimmune response against components of myelin, which is thought to contribute to disease pathogenesis.

T-cell anergy

A state of T-cell unresponsiveness to stimulation with antigen. It can be induced by stimulation with a large amount of specific antigen in the absence of the engagement of co-stimulatory molecules.

WNT

WNT proteins are glycoproteins related to the Drosophila melanogaster protein Wingless, a ligand that regulates the temporal and spatial development of the embryo. WNT-mediated signalling has been shown to regulate cell-fate determination, proliferation, adhesion, migration and polarity during development. In addition to their crucial role in embryogenesis, WNT proteins and their downstream signalling molecules have been implicated in tumorigenesis and have causative roles in human colon cancers.

Graft-versus-host disease

(GVHD). A disease that results from the immunological attack by donor allogeneic T cells that are transferred with the allograft (such as bone marrow, liver or gut) of target recipient organs or tissues (such as the skin or gut). GVHD occurs in graft recipients who cannot eliminate the host-reactive donor T cells, owing to immunosuppression, immunological immaturity or tolerance of the recipient.

Histocompatibility antigens

Polymorphic peptides derived from normal cellular proteins that can be recognized in the context of MHC molecules. They get their name because they are responsible for the compatibility, or rather the lack of it, of the tissues of genetically different individuals. Immune responses specific for these polymorphic antigens can result in graft-versus-host reactions, graft rejection or beneficial anti-tumour responses.

Graft-versus-leukaemia effect

An alloimmune attack against recipient haematopoietic neoplasms, which is mounted by donor immune cells in an allogeneic haematopoietic stem-cell transplant. With the exception of T-cell-depleted haploidentical allogeneic stem-cell transplants, wherein graft-versus-leukaemia effects can be mediated by alloreactive natural killer cells, the graft-versus-leukaemia response is mediated by αβ T cells in the donor allograft.

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Uccelli, A., Moretta, L. & Pistoia, V. Mesenchymal stem cells in health and disease. Nat Rev Immunol 8, 726–736 (2008). https://doi.org/10.1038/nri2395

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