Reinventing mesenchymal stromal cells.

The life-saving impact of chemotherapy and radiation has been as remarkable and momentous as any advance in the history of medicine. This becomes even more signifi cant when we remind ourselves that 50 years ago nearly all leukemias, lymphomas and aggressive solid tumors were fatal, and that nearly everything in oncology before the 20th century was a placebo. However, unintended collateral damage by chemotherapy and radiation to healthy tissues of patients has limited the benefi cial impact of these successes in oncology and in the related fi eld of hematopoietic cell transplantation (HCT). HCT has been a life-saving treatment for many patients with malignant as well as non-malignant, yet equally lethal, diseases and conditions, such as bone marrow failure (e.g. acquired idiopathic severe aplastic anemia, osteopetrosis, Fanconi anemia and dyskeratosis congenita), hemoglobinopathies (e.g. sickle cells disease and thalassemia), immunodefi ciencies (e.g. X-linked defi ciency in the common cytokine receptor gamma chain), and lysosomal (e.g. mucopolysaccharidosis type I – Hurler syndrome), peroxisomal (e.g. childhood cerebral adrenoleukodystrophy) and extracellular matrix (e.g. severe forms of epidermolysis bullosa) disorders (1,2). To limit tissue toxicity, in principle at least two major, but not mutually exclusive, approaches are possible: targeted therapy of cancer (e.g. Ph (Philadelphia (chromosome)) leukemia treatment with anti-BCR-ABL (Breakpoint Cluster Region-Abelson (gene)) antibody) (3) and targeted conditioning for HCT (e.g. immunoablation of hematopoietic stem cells with anti-c-kit antibody) (4); or injury protection and enhancement of tissue repair. During the last decade, the most popular cells for the latter concept have been mesenchymal stromal cells (MSC) (5). Their function in vivo is not well defi ned, but they are likely to be critical for a number of physiologic processes. One example is a support for blood-forming cells in the bone marrow hematopoietic niche, where they are ‘ a drugstore ’ , supplying neighboring cells with growth factors, adhesion molecules and homing cytokines. MSC can function as immune modulator cells and are being used extensively for the prevention and treatment of graft-versus-host disease, the main immune complication of HCT. Also, MSC home preferentially to sites of injury and, in several pre-clinical models and clinical trials of organ damage (e.g. heart, lung, kidney, pancreas, intestine, bone and skin), have been shown to mediate tissue healing. Contrary to original expectations, donor MSC do not appear to replace the damaged cells, but rather use paracrine mediators to recruit the recipients ’ cells into a regenerative microenvironment, which in turn limits apoptosis, promotes angiogenesis, and aids in productive tissue repair (6). Two recent reports in Cytotherapy explore this regenerative capability of human MSC in mice treated with high doses of radiation or chemotherapy. Di et al. (7) asked whether chemotherapy-induced injury in mice could be alleviated by infusion of MSC from human cord blood. They treated mice with doxorubicin, a chemotherapy medication associated with a stereotypical toxicity profi le in bone marrow, heart and intestines. Infusion of MSC not only decreased the degree of damage in these organs, but also increased overall survival in mice that had Cytotherapy, 2012; 14: 388–390