Ko-Jiunn Liu

Immunomodulatory properties of human adult and fetal multipotent mesenchymal stem cells

In recent years, a large number of studies have contributed to our understanding of the immunomodulatory mechanisms used by multipotent mesenchymal stem cells (MSCs). Initially isolated from the bone marrow (BM), MSCs have been found in many tissues but the strong immunomodulatory properties are best studied in BM MSCs. The immunomodulatory effects of BM MSCs are wide, extending to T lymphocytes and dendritic cells, and are therapeutically useful for treatment of immune-related diseases including graft-versus-host disease as well as possibly autoimmune diseases. However, BM MSCs are very rare cells and require an invasive procedure for procurement. Recently, MSCs have also been found in fetal-stage embryo-proper and extra-embryonic tissues, and these human fetal MSCs (F-MSCs) have a higher proliferative profile, and are capable of multilineage differentiation as well as exert strong immunomodulatory effects. As such, these F-MSCs can be viewed as alternative sources of MSCs. We review here the current understanding of the mechanisms behind the immunomodulatory properties of BM MSCs and F-MSCs. An increase in our understanding of MSC suppressor mechanisms will offer insights for prevalent clinical use of these versatile adult stem cells in the near future.

Brief Report—Human Embryonic Stem Cell‐Derived Mesenchymal Progenitors Possess Strong Immunosuppressive Effects Toward Natural Killer Cells as Well as T Lymphocytes

The derivation of mesenchymal progenitors from human embryonic stem cells (hESCs) has recently been reported. We studied the immune characteristics of these hESC‐derived mesenchymal progenitors (EMPs) and their interactions with T lymphocytes and natural killer cells (NKs), two populations of lymphocytes with important roles in transplantation immunology. EMPs express a number of bone marrow mesenchymal stromal cell (BMMSC) markers, as well as the hESC marker SSEA‐4. Immunologically, EMPs do not express HLA‐DR or costimulatory molecules. On the other hand, HLA‐G, a nonclassic MHC I protein involved in mediating maternal‐fetal tolerance, can be found on the surface of EMPs, and its expression is increased after interferon‐γ stimulation. EMPs can suppress CD4+ or CD8+ lymphocyte proliferation, similar to BMMSCs. However, EMPs are more resistant to NK‐mediated lysis than BMMSCs and can suppress the cytotoxic effects of activated NKs, as well as downregulating the NK‐activating receptors NKp30 and NKp46. With their broad immunosuppressive properties, EMPs may represent a new potential cell source for therapeutic use. STEM CELLS 2009;27:451–456

Human mesenchymal stem cells (MSCs) for treatment towards immune- and inflammation-mediated diseases: review of current clinical trials

Human mesenchymal stem cells (MSCs) are multilineage somatic progenitor/stem cells that have been shown to possess immunomodulatory properties in recent years. Initially met with much skepticism, MSC immunomodulation has now been well reproduced across tissue sources and species to be clinically relevant. This has opened up the use of these versatile cells for application as 3rd party/allogeneic use in cell replacement/tissue regeneration, as well as for immune- and inflammation-mediated disease entities. Most surprisingly, use of MSCs for in immune-/inflammation-mediated diseases appears to yield more efficacy than for regenerative medicine, since engraftment of the exogenous cell does not appear necessary. In this review, we focus on this non-traditional clinical use of a tissue-specific stem cell, and highlight important findings and trends in this exciting area of stem cell therapy.

Differentiation of Mesenchymal Stem Cells from Human Induced Pluripotent Stem Cells Results in Downregulation of c‐Myc and DNA Replication Pathways with Immunomodulation Toward CD4 and CD8 Cells

Multilineage tissue‐source mesenchymal stem cells (MSCs) possess strong immunomodulatory properties and are excellent therapeutic agents, but require constant isolation from donors to combat replicative senescence. The differentiation of human induced pluripotent stem cells (iPSCs) into MSCs offers a renewable source of MSCs; however, reports on their immunomodulatory capacity have been discrepant. Using MSCs differentiated from iPSCs reprogrammed using diverse cell types and protocols, and in comparison to human embryonic stem cell (ESC)‐MSCs and bone marrow (BM)‐MSCs, we performed transcriptome analyses and assessed for functional immunomodulatory properties. Differentiation of MSCs from iPSCs results in decreased c‐Myc expression and its downstream pathway along with a concomitant downregulation in the DNA replication pathway. All four lines of iPSC‐MSCs can significantly suppress in vitro activated human peripheral blood mononuclear cell (PBMC) proliferation to a similar degree as ESC‐MSCs and BM‐MSCs, and modulate CD4 T lymphocyte fate from a type 1 helper T cell (Th1) and IL‐17A‐expressing (Th17) cell fate to a regulatory T cell (Treg) phenotype. Moreover, iPSC‐MSCs significantly suppress cytotoxic CD8 T proliferation, activation, and differentiation into type 1 cytotoxic T (Tc1) and IL‐17‐expressing CD8 T (Tc17) cells. Coculture of activated PBMCs with human iPSC‐MSCs results in an overall shift of secreted cytokine profile from a pro‐inflammatory environment to a more immunotolerant milieu. iPSC‐MSC immunomodulation was also validated in vivo in a mouse model of induced inflammation. These findings support that iPSC‐MSCs possess low oncogenicity and strong immunomodulatory properties regardless of cell‐of‐origin or reprogramming method and are good potential candidates for therapeutic use. Stem Cells 2018;36:903–914

Assessment of the Immunomodulatory Properties of Human Mesenchymal Stem Cells (MSCs).

The immunomodulatory properties of multilineage human mesenchymal stem cells (MSCs) appear to be highly relevant for clinical use towards a wide-range of immune-related diseases. Mechanisms involved are increasingly being elucidated and in this article, we describe the basic experiment to assess MSC immunomodulation by assaying for suppression of effector leukocyte proliferation. Representing activation, leukocyte proliferation can be assessed by a number of techniques, and we describe in this protocol the use of the fluorescent cellular dye carboxyfluorescein succinimidyl ester (CFSE) to label leukocytes with subsequent flow cytometric analyses. This technique can not only assess proliferation without radioactivity, but also the number of cell divisions that have occurred as well as allowing for identification of the specific population of proliferating cells and intracellular cytokine/factor expression. Moreover, the assay can be tailored to evaluate specific populations of effector leukocytes by magnetic bead surface marker selection of single peripheral blood mononuclear cell populations prior to co-culture with MSCs. The flexibility of this co-culture assay is useful for investigating cellular interactions between MSCs and leukocytes.