Regenerative stromal cell therapy in allogeneic hematopoietic stem cell transplantation: current impact and future directions

Abstract

Regenerative stromal cell therapy (RSCT) has the potential to become a novel therapy for preventing and treating acute graft-versus-host disease (GVHD) in the allogeneic hematopoietic stem cell transplant (HSCT) recipient. However, enthusiasm for using RSCT in allogeneic HSCT has been tempered by limited clinical data and poorly defined in vivo mechanisms of action. As a result, the full clinical potential of RSCT in supporting hematopoietic reconstitution and as treatment for GVHD remains to be determined. This manuscript reviews the immunomodulatory activity of regenerative stromal cells in preclinical models of allogeneic HSCT, and emphasizes an emerging literature suggesting that microenvironment influences RSC activation and function. Understanding this key finding may ultimately define the proper niche for RSCT in allogeneic HSCT. In particular, mechanistic studies are needed to delineate the in vivo effects of RSCT in response to inflammation and injury associated with allogeneic HSCT, and to define the relevant sites of RSC interaction with immune cells in the transplant recipient. Furthermore, development of in vivo imaging technology to correlate biodistribution patterns, desired RSC effect, and clinical outcome will be crucial to establishing dose-response effects and minimal biologic dose thresholds needed to advance translational treatment strategies for complications like GVHD.

Figure 1. Mesenchymal stromal cells: mesenchymal stem cells and multipotent adult progenitor cells

General comparisons between two specific types of mesenchymal stromal cells are provided. Refer to text for details. Photographs of MSCs (162) and MAPCs (36) reprinted with permission. Prochymal^™ is a mesenchymal stem cell (MSC)-based product GMP-manufactured by Osiris Therapeutics, Inc. (Baltimore, MD). MultiStem^® is a multipotent adult progenitor cell (MAPC)-based product GMP-manufactured by Athersys, Inc. (Cleveland, OH). Note: ⁺⁺ Population doubling (PD) limit is defined as the maximum number of PDs in which the respective stromal cell maintains telomere length, cytogenetic stability, and multi-lineage differentiation potential in ex vivo culture conditions. These limits are variable and dependent upon the expansion protocol used, the age and condition of the donor, and the frequency of stromal cells in the bone marrow. Abbreviations: MSC = mesenchymal stem cell; MAPC = multipotent adult progenitor cell; μM = micron.

Figure 2. Emerging model of mesenchymal stromal cell activation and function in the context of tissue injury and/or inflammation

Migrating hematopoietic and non-hematopoietic cells home to sites of tissue injury and inflammation along gradients created by inflammatory chemokines and danger signals. Resident hematopoietic (macrophages/monocytes, dendritic cells) and non-hematopoietic (stromal cells) cells are also activated by this inflammatory milieu. Activated mesenchymal stromal cells (MSCs) produce immunomodulatory soluble factors (e.g., HGF, HO-1, IDO, IL-10, PGE2, TGF-β) that inhibit antigen-presenting cell (APC) maturation and development, inhibit T-cell activation and function and induce regulatory dendritic cell (DC) and T-cell phenotypes. Thus, “net” MSC immunomodulation likely reflects the summation of modulatory cellular and soluble factors within the microenvironment that can influence MSC activation and function. Other potential desirable effects mediated by MSCs during allogeneic stem cell transplant area also shown.