Ex Vivo Mesenchymal Stem Cell Therapy to Regenerate Machine Perfused Organs

Abstract

Transplantation represents the treatment of choice for many end-stage diseases but is limited by the shortage of healthy donor organs. Ex situ normothermic machine perfusion (NMP) has the potential to extend the donor pool by facilitating the use of marginal quality organs such as those from donors after cardiac death (DCD) and extended criteria donors (ECD). NMP provides a platform for organ quality assessment but also offers the opportunity to treat and eventually regenerate organs during the perfusion process prior to transplantation. Due to their anti-inflammatory, immunomodulatory and regenerative capacity, mesenchymal stem cells (MSCs) are considered as an interesting tool in this model system. Only a limited number of studies have reported on the use of MSCs during ex situ machine perfusion so far with a focus on feasibility and safety aspects. At this point, no clinical benefits have been conclusively demonstrated, and studies with controlled transplantation set-ups are urgently warranted to elucidate favorable effects of MSCs in order to improve organs during ex situ machine perfusion.

Keywords: machine perfusion; mesenchymal stem cells; regeneration.

Figure 1

Effects of MSCs on organ regeneration through immunomodulatory and other effects. MSCs suppress T cell, B cell, and natural killer (NK) cell proliferation. They may induce regulatory T cell differentiation via secretion of indoleamine 2,3-dioxygenase (IDO) and human leukocyte antigen-G5 (HLA-G5), have an impact on the maturation of monocytes into dendritic cells, and inhibit NK and T cell function. Through secretion of soluble factors, such as growth factors, cytokines, and chemokines, MSCs contribute to tissue repair, promote angiogenesis, and prevent cell apoptosis and formation of fibrosis. (Figure created with https://biorender.com, accessed on 21 March 2021).

Figure 2

Minimal criteria for defining multipotent mesenchymal stem cells, according to the International Society for Cellular Therapy (ISCT). (Figure created with https://biorender.com, accessed on 21 March 2021). (1) MSCs must be plastic adherent in standard culture conditions. (2) Expression of CD73, CD90, CD105, and absence of the expression of hematopoietic cell surface markers CD34, CD45, CD11b or CD14, CD19 or CD79a, and HLA-DR. (3) Upon specific stimulation, MSCs must differentiate into osteoblasts, adipocytes, or chondrocytes.

Figure 3

Normothermic machine perfusion as a novel platform to treat and regenerate organs outside the human body. MSCs can be delivered directly into the vasculature of the liver by addition into the circulating perfusate. This concept may help to overcome issues of MSC trafficking and homing (Figure created with https://biorender.com, accessed on 21 March 2021).