Interaction of allogeneic adipose tissue-derived stromal cells and unstimulated immune cells in vitro: the impact of cell-to-cell contact and hypoxia in the local milieu

Abstract

Multipotent mesenchymal stem cells (MSCs) are an attractive tool for cell therapy and regenerative medicine. Being applied in vivo, allogeneic MSCs are faced with both activated and unstimulated immune cells. The effects of MSCs on activated immune cells are well described and are mainly suppressive. Less is known about the interaction of MSCs with unstimulated immune cells. We evaluated the contribution of tissue-related O level ("physiological" hypoxia-5% O) and cell-to-cell contact to the interaction between allogeneic adipose tissue-derived MSCs (ASCs) and unstimulated peripheral blood mononuclear cells (PBMCs). Under both O levels, ASCs affected the immune response by elevating the proportion of CD69+ T cells and modifying the functional activity of unstimulated PBMCs, providing a significant reduction of ROS level and activation of lysosome compartment. "Physiological" hypoxia partially attenuated the ASC modulation of PBMC function, reducing CD69+ cell activation and more significantly supressing ROS. In direct co-culture, the ASC effects were more pronounced. PBMC viability was preferentially maintained, and the lymphocyte subset ratio was altered in favour of B cells. Our findings demonstrate that allogeneic ASCs do not enhance the activation of unstimulated immune cells and can provide supportive functions. The "hypoxic" phenotype of ASCs may be more "desirable" for the interaction with allogeneic immune cells that may be required in cell therapy protocols.

ADSC-conditioned media elicit an ex vivo anti-inflammatory macrophage response

“…Due to the demographics of the population surrounding Tygerberg hospital, the participants included in this study were of mixed ancestry. This specific ethnic population is known to have a genetic predisposition and especially females have a considerable risk to develop type 2 diabetes (Goedecke et al 2017). The data presented in this study are thus specific for this population and should be interpreted as such.…”

Differentiation and Functionality of Bone Marrow-Derived Mast Cells Depend on Varying Physiologic Oxygen Conditions

“…Culturing embryonic stem cells at 5% oxygen retains their pluripotency ( 45 ). Importantly, Gornostaeva and colleagues conclude from their results that “the ‘hypoxic’ phenotype of ASCs (allogeneic adipose tissue-derived multipotent mesenchymal stem cells) may be more ‘desirable’ for the interaction with allogeneic immune cells” ( 46 ). In addition, oxygen is considered as an important signaling molecule, which has an integral role in the hematopoietic stem cell maintenance as well as in stem cell proliferation and differentiation ( 47 ).…”

Factors Defining Human Adipose Stem/Stromal Cell Immunomodulation in Vitro

“…A number of investigators addressed the immunoregulatory impact of hASCs under hypoxic (1–7%) vs. normoxic or ambient oxygen (O2) levels (20%) [ 58 , 68 – 73 ]. Low O2 level is typical for the putative site of the MSC-T cell interactions [ 72 ].…”

“…At a hASC: immune cell ratio ranging from (1:1–1:25), hASCs exhibit potent immunosuppressive properties on diverse immune cell types. Substantial literature studies reported maximum hASC immunosuppression at high ASC: immune cell ratio (from 1:1 to 1:10) [ 6 , 10 – 12 , 14 , 21 , 24 , 25 , 33 , 36 , 51 , 58 , 61 , 64 , 67 , 73 , 79 – 88 ]. Others reported maximum suppression at lower ratios (1:20) [ 89 ] or (1:25) [ 23 , 32 , 35 , 90 ].…”