Wharton's jelly-derived stromal cells and their cell therapy applications in allogeneic haematopoietic stem cell transplantation

Abstract

For decades, mesenchymal stromal cells (MSCs) have been of great interest in the fields of regenerative medicine, tissue engineering and immunomodulation. Their tremendous potential makes it desirable to cryopreserve and bank MSCs to increase their accessibility and availability. Postnatally derived MSCs seem to be of particular interest because they are harvested after delivery without ethical controversy, they have the capacity to expand at a higher rate than adult-derived MSCs, in which expansion decreases with ageing, and they have demonstrated immunological and haematological supportive properties similar to those of adult-derived MSCs. In this review, we focus on MSCs obtained from Wharton's jelly (the mucous connective tissue of the umbilical cord between the amniotic epithelium and the umbilical vessels). Wharton's jelly MSCs (WJ-MSCs) are a good candidate for cellular therapy in haematology, with accumulating data supporting their potential to sustain haematopoietic stem cell engraftment and to modulate alloreactivity such as Graft Versus Host Disease (GVHD). We first present an overview of their in-vitro properties and the results of preclinical murine models confirming the suitability of WJ-MSCs for cellular therapy in haematology. Next, we focus on clinical trials and discuss tolerance, efficacy and infusion protocols reported in haematology for GVHD and engraftment.

Keywords: Wharton's jelly; applications; cell therapy; graft versus host disease; mesenchymal stem cells; stem cell transplantation; stromal cells.

FIGURE 1

WJ‐MSCs support haematopoiesis and modulate immunity via soluble factors and cell‐cell contact. Upper: WJ‐MSCs secrete growth factors that may enhance haematopoietic cell renewal or stemness, and they may create a fibronectin network that supports haematopoietic cell homeostasis. Thus, they are of interest in the treatment of poor graft function after HSCT. IL‐6: Interleukin‐6, SCF: stem‐cell factor, M‐CSF: macrophage colony‐stimulating factor, G‐CSF: granulocyte colony‐stimulating factor, GM‐CSF: granulocyte macrophage colony‐stimulating factor, Flt3: Fms‐like tyrosine kinase 3; Lower: WJ‐MSCs secrete cytokines and other molecules that decrease activated T‐cell proliferation, or induce Tregs, and act on other immune cells. They also produce cytosolic IDO, an enzyme that depletes tryptophan in the medium and converts tryptophan into secreted metabolites (like kynurenine) that prevent T‐cell proliferation. WJ‐MSCs also express several membrane molecules that interact with activated T cells to induce exhaustion or apoptosis, or to prevent T‐cell activation. The expression of soluble and membrane factors varies according to the level of inflammation in the environment. These properties make WJ‐MSCs good candidates for GVHD prophylaxis or cure, for graft rejection prophylaxis, and for some disorders of uncontrolled inflammation, such as haemorrhagic cystitis. PGE2, prostaglandin E2; HGF, hepatic growth factor; IL, interleukin; TGF β1, transforming growth factor β1; HLA, human leukocyte antigen; PDL (1/2), programmed‐death ligand; VCAM, vascular cell adhesion molecule; ICAM, intercellular adhesion molecule

FIGURE 2

WJ‐MSCs use several membrane and soluble factors to modulate the immune system. WJ‐MSCs regulate immunity through cell‐cell contact with T cells: PD‐L1 (programmed‐death ligand 1), galectins (1, 3, 9), VCAM 1 (vascular cell adhesion molecule 1), ICAM 1 (intercellular adhesion molecule 1), HLA (human leukocyte antigen)‐G1, and CD73. They also express the usual HLA class I molecules and do not express costimulatory molecules. They may express CD40 and HLA class II molecules in an inflamed environment. They produce many soluble factors: PGE2 (prostaglandin E2), HGF (hepatocyte growth factor), IL (interleukins) −6 and −10, TGFβ1 (transforming growth factor β1), soluble HLA‐G5, and soluble galectins (1, 3 and 9). These soluble factors decrease T‐cell proliferation, induce T‐cell apoptosis and polarize T cells to become regulatory T cells (Tregs). They also prevent dendritic cell (DC) maturation and modify NK and B‐cell functions, giving them a ‘regulatory’ phenotype. Moreover, WJ‐MSCs express IDO (indoleamine 2–3 dioxygenase), in their cytosol. This enzyme is responsible of tryptophan depletion in the medium, and tryptophan‐metabolite production (kynurenine, 3‐hydroxykynurenine and kynurenic acid)