Allogenic Use of Human Placenta-Derived Stromal Cells as a Highly Active Subtype of Mesenchymal Stromal Cells for Cell-Based Therapies

Abstract

The application of mesenchymal stromal cells (MSCs) from different sources, including bone marrow (BM, bmMSCs), adipose tissue (atMSCs), and human term placenta (hPSCs) has been proposed for various clinical purposes. Accumulated evidence suggests that the activity of the different MSCs is indirect and associated with paracrine release of pro-regenerative and anti-inflammatory factors. A major limitation of bmMSCs-based treatment for autologous application is the limited yield of cells harvested from BM and the invasiveness of the procedure. Similar effects of autologous and allogeneic MSCs isolated from various other tissues were reported. The easily available fresh human placenta seems to represent a preferred source for harvesting abundant numbers of human hPSCs for allogenic use. Cells derived from the neonate tissues of the placenta (f-hPSC) can undergo extended expansion with a low risk of senescence. The low expression of HLA class I and II on f-hPSCs reduces the risk of rejection in allogeneic or xenogeneic applications in normal immunocompetent hosts. The main advantage of hPSCs-based therapies seems to lie in the secretion of a wide range of pro-regenerative and anti-inflammatory factors. This renders hPSCs as a very competent cell for therapy in humans or animal models. This review summarizes the therapeutic potential of allogeneic applications of f-hPSCs, with reference to their indirect pro-regenerative and anti-inflammatory effects and discusses clinical feasibility studies.

Keywords: adipose tissue stromal cells (atMSCs); bone marrow MSCs (bmMSC); cell-based immune modulation; mesenchymal stromal/stem cells (MSC); placenta-derived mesenchymal stromal cells (hPSCs/pMSCs); pro-regenerative effects; regenerative cell therapy; xenogeneic cell delivery.

Figure 1

A shared phenotype of MSCs surface markers and secretome from different cell sources. MSCs from different sources seem to have a wide range of shared features in their cell surface markers, secretion profile of growth factors, cytokines, and miRs. The significant difference between the MSCs from different tissue sources may lie predominantly in the levels and profile of the factors secreted and the degree of their activation by the induction of these factors secretion. The data presented were assembled mainly based on the reviews on MSCs of Pittenger et al. [87], Eleuteri and Fierabraci [88], and on the studies on PSCs of Pinzur et al. [114] and Adani et al. [116].

Figure 2

The structure of full-term placenta and the tissues from where hPSCs are isolated. The structure of the placenta. The placenta is composed of the fetal and maternal tissues interconnected with a border and separate network of blood vessels. It is clearly demonstrated that the source of the stromal cells, in case the tissue samples taken are not carefully dissected out, may contain the combination of the fetal and maternal cells from two separate individuals.

Figure 3

Difference of shape of cultured PSCs vs bmMSCs. The difference in the shape of freshly cultured isolated human hPSCs and human skin fibroblast (HF). The hPSCs spread in culture can reach a size of up to ~100 µm, while the fibroblasts are much smaller in size and grow in much more condensed cultures. Nevertheless, both cell types show almost similar surface markers, except for CD166, which is expressed more in PSCs (see also Figure 1).

Figure 4

An example of successful hPSCs-based treatment for mitigation of acute radiation syndrome by remote PSCs injection. Example of the indirect systemic effect of the f-hPSCs as demonstrated in studies on the mitigation of acute radiation syndrome. Mice were total body irradiated with a lethal dose and then treated by fetal human PSCs. The X/Y chromosomes staining and cell surface markers profile of the cells are presented in (A). The CFSE-stained f-hPSCs seemed to stay in the injection site in the muscle, from where their secretome must have reached the circulation to help regenerate the BM (B). The mice treated with f-hPSCs had better mitigation of ARS than PSCs isolated from the maternal placenta (C), with impressive recovery of white blood cells, platelets, and red blood cells (D–F). (G) The cytokine production (shown as yellow peak) represents the kinetics of major related secretome in the plasma. The peak of the kinetics of plasma levels of the f-hPSCs secreted human cytokines coincided with the apparent recovery of the cell-treated pre-irradiated mice and the increase of their BM progenitors (red line) in comparison with the progenitor number in the few surviving non-treated pre-irradiated mice (green line). The figure presented was re-plotted based on the data in the reports of Gaberman et al. [206], Pinzur et al. [114], and Adani et al. [116]. * indicates a significant difference between cell-treated (+IM PSC) and sham- treated (vehicle) animals.