Mechanism of action of somatic stem cell treatments: towards the concept of therapeutic plasticity

Abstract

The initial perception that transplantation of stem cells could serve only to replace damaged cells has continued to be modifi ed as evidence for a protective multifaceted function of transplanted cells has emerged. Neural stem/precursor cells (NPC) were the fi rst to be shown to use this strategy to protect the central nervous system (CNS) from infl ammatory insults (1 – 5). Subsequently similar functions by other types of somatic stem cells (e.g. mesenchymal stromal cells; MSC) have been described (6). Currently the ability of transplanted stem cells to protect tissues from diverse injury using multifaceted ‘ bystander strategies ’ has been substantiated in several experiments. Somatic stem cells promote CNS repair following intralesional as well as systemic injection by producing in situ a milieu of protective molecules whose release is regulated, both temporally and spatially, by environmental demands. The milieu contains immunomodulatory substances, trophic growth factors, stem cell regulators, angiogenic factors, scavengers, etc.: all molecules constitutively expressed by somatic stem cells for maintaining tissue homeostasis during development and in adult life. The concept of ‘ therapeutic platicity ’ that is now emerging (7) also reconciles data showing that stem cells other than NPC, although endowed with negligible transdifferentiation capability, may have a benefi cial role in CNS repair. In four articles of this issue of Cytotherapy the concept of therapeutic plasticity of somatic stem cells is presented further. Although these reports do not completely clarify the mechanisms underlying this therapeutic plasticity, they demonstrate that transplantation of various somatic stem cells via different routes ameliorates diverse neurologic diseases without an overt terminal differentiation and functional integration of the transplanted cells. Alexanian et al. (8) observe that delayed intralesional transplantation of human glial-restricted NPC in rats affected by thoracic spinal cord injury ameliorates sensorimotor defi cits. He et al. (9) report that bone marrow (BM)-derived MSC and endothelial progenitor cells transplanted intravenously (i.v.) protect rats from focal ischemia via the secretion of different combinations of growth factors. Interestingly, an additive benefi cial effect was observed when the two different cell sources were co-transplanted. Li et al. (10) focus on a mouse model of muscular dystrophy where mean survival as well as loss of dystrophin and utrophin expression is delayed by i.v. transplantation of rat-derived MSC. Attar et al. (11) describe preliminary results of intralesional transplantation of BM-derived hematopoietic stem cells along with BM-derived mononuclear cells in four patients with spinal cord injury. Although the possibility of using bystander strategies as protection from tissue injury appears to be a very promising therapeutic use of somatic stem cells, we still need to resolve unsolved key questions before clinical translation. One crucial question is whether to transplant the cells heterotopically or homotopically. Transplantation is not without risks: co-transplantation of NPC and pancreatic islet cells under the kidney capsule of diabetic mice induced the generation, at the site of cell transplantation, of insulin-induced neuroblastoma-like neoplasms (12). Intracardiac transplantation of stem cell factor-overexpressing MSC into mice with myocardial infarction promoted the formation of a chest wall-invading soft tissue sarcoma (13). The unregulated transplantation Cytotherapy, 2011; 13: 6–7