Are clinical trials with mesenchymal stem/progenitor cells too far ahead of the science? Lessons from experimental hematology

Abstract

The cells referred to as mesenchymal stem/progenitor cells (MSCs) are currently being used to treat thousands of patients with diseases of essentially all the organs and tissues of the body. Strikingly positive results have been reported in some patients, but there have been few prospective controlled studies. Also, the reasons for the beneficial effects are frequently unclear. As a result there has been a heated debate as to whether the clinical trials with these new cell therapies are too far ahead of the science. The debate is not easily resolved, but important insights are provided by the 60-year history that was required to develop the first successful stem cell therapy, the transplantation of hematopoietic stem cells. The history indicates that development of a dramatically new therapy usually requires patience and a constant dialogue between basic scientists and physicians carrying out carefully designed clinical trials. It also suggests that the field can be moved forward by establishing better records of how MSCs are prepared, by establishing a large supply of reference MSCs that can be used to validate assays and compare MSCs prepared in different laboratories, and by continuing efforts to establish in vivo assays for the efficacy of MSCs.

Keywords: Hematopoietic stem cells; Need for scientific dialogue; New clinical therapies.

Figure 1

Abbreviated summary of the development of successful therapies with hematopoietic stem cell transplantation. For more complete accounts see ,. Abbreviations: BMT, bone marrow transplant; CFU, colony forming units; GVHD, graft versus host disease; HLA, human leukocyte antigens.

Figure 2

Schematics illustrating differences between HSCs and MSCs. (A): The stem cell niche hypothesis (after Schofield 21). Replicating hematopoietic stem cells (HSCs) that remain tethered in the niche retain stem cell potential, while those leaving the niche proliferate, differentiate, and lose their regenerative potential unless they reoccupy an available stem cell niche and revert back to HSCs. (B): Schematic summary of how MSCs can produce improvements in animal models for human diseases. As discussed in text, MSCs can be activated by signals from injured tissues, such as proinflammatory cytokines, pathogen-associated molecular pattern molecules, and damage-associated molecular pattern molecules. The several forms of activated MSCs then modulate inflammation, immunity, apoptosis, proliferation, differentiation, and other processes by secreting paracrine factors such as CCL2 (monocyte chemotactic protein 1), prostaglandin E2 (PGE2), indoleamine 2,3-dioxygenase (IDO), vascular endothelial growth factor (VEGF), TNFalpha stimulated gene/protein 6 (TSG-6), and stanniocalcin 1 (STC-1). They also can establish cell-to-cell contacts or secrete microvesicles that transfer micro-RNAs and mitochondria. Abbreviation: MSCs, mesenchymal stem cells.