Human placenta‐derived adherent cells induce tolerogenic immune responses

Abstract

Human placenta-derived adherent cells (PDAC cells) are a culture expanded, undifferentiated mesenchymal-like population derived from full-term placental tissue, with immunomodulatory and anti-inflammatory properties. PDA-001 (cenplacel-L), an intravenous formulation of PDAC cells, is in clinical development for the treatment of autoimmune and inflammatory diseases. To elucidate the mechanisms underlying the immunoregulatory properties of PDAC cells, we investigated their effects on immune cell populations, including T cells and dendritic cells (DC) in vitro and in vivo. PDAC cells suppressed T-cell proliferation in an OT-II T-cell adoptive transfer model, reduced the severity of myelin oligodendrocyte glycoprotein peptide-induced experimental autoimmune encephalomyelitis and ameliorated inflammation in a delayed type hypersensitivity response model. In vitro, PDAC cells suppressed T-cell proliferation and inhibited Th1 and Th17 differentiation. Analysis of tissues derived from PDAC cell-treated animals revealed diminished CD86 expression on splenic DC, suggesting that they can also modulate DC populations. Furthermore, PDAC cells modulate the differentiation and maturation of mouse bone marrow-derived DC. Similarly, human DC differentiated from CD14+ monocytes in the presence of PDAC cells acquired a tolerogenic phenotype. These tolerogenic DC failed to induce allogeneic T-cell proliferation and differentiation toward Th1, but skewed T-cell differentiation toward Th2. Inhibition of cyclo-oxygenase-2 activity resulted in a significant, but not complete, abrogation of PDAC cells' effects on DC phenotype and function, implying a role for prostaglandin E2 in PDAC-mediated immunomodulation. This study identifies modulation of DC differentiation toward immune tolerance as a key mechanism underlying the immunomodulatory activities of PDAC cells.

Angiogenic properties of human placenta-derived adherent cells and efficacy in hindlimb ischemia

“…The cells are anchorage dependent in culture and adhere to plastic during expansion in vitro. 7 PDAC-mediated activities have been studied in vitro, in animal models, and in clinical trials and display immunomodulatory, anti-inflammatory, proregenerative, and neuroprotective properties, [7][8][9][10] suggesting that the cells may have potential utility across a variety of disease indications. PDA-002, an intramuscular formulation of PDACs, is in clinical development for the treatment of peripheral arterial disease with diabetic foot ulcer (http:// clinicaltrials.gov/show/NCT01859117).…”

“…6 Placenta-derived adherent cells (PDACs) are a cultureexpanded, undifferentiated mesenchymal-like population derived from full-term placental tissue. 7 The cells have the genotype of the newborn and display features characteristic of MSCs, but with a unique phenotype associated with their placental origin. The cells are anchorage dependent in culture and adhere to plastic during expansion in vitro.…”

Human Placenta-Derived Adherent Cells Improve Cardiac Performance in Mice With Chronic Heart Failure

“…celgene.com) in a Good Manufacturing Practices-compliant facility [13]. These cells were isolated by mechanical and enzymatic digestion of postpartum human placenta, were karyotypically normal, and had the genotype of the newborn and the nominal phenotype …”

“…PDAC-mediated activities have been studied in both in vitro and animal models, and the results have suggested that the cells might have potential utility across a variety of disease indications. PDA-001 (cenplacel-L), an intravenous formulation of PDAC cells composed of CD44 + , and CD45 2 cells, is in clinical development for the treatment of autoimmune and inflammatory diseases [13,14]. The primary objective of the present study was to provide proof of concept of the utility of PDA-001 in chronic heart failure (CHF) using a mouse model of CHF.…”

“…Human placenta-derived adherent cells (PDACs) are a culture expanded, undifferentiated mesenchymal-like population derived from fullterm placental tissue and display immunomodulatory, anti-inflammatory, pro-regenerative, angiogenic, and neuroprotective properties [10][11][12][13]. The cells are anchorage-dependent in culture and will adhere to the plastic surface during expansion culture in vitro.…”