Pharmacological Modulation of Stem Cell Function

P.      Romagnani; L.      Lasagni; B.      Mazzinghi; E.      Lazzeri; S.      Romagnani

Abstract

The discovery of stem cells (SC) has shed new light on the understanding of mechanisms responsible for ischemic and degenerative disorders, and opened a new field for regenerative medicine. Furthermore, dysregulation of SC self-renewal and their transformation seem to be involved also in the development of cancer, suggesting that pharmacological treatment devoted to regulate SC genomic and phenotypic functions might represent a potential new strategy even for the treatment of neoplastic disorders. SC display a promiscuous set of transcription factors and an open chromatin structure which are required to maintain their multipotentiality, while they are progressively quenched during differentiation into specific multiple lineages. The mechanisms that govern stem cell fate decisions are under tight control but remain potentially alterable. Recent studies have shown that several currently used drugs such as colony stimulating factors, statins, angiotensin-II receptor antagonists/ACEinhibitors, Erythropoietin, nitric oxide donors, estrogens and glitazones, have modulatory activity on SC functions. These drugs mostly enhance SC survival and mobilization. Furthermore, a series of new pharmacological agents such as the chemokine receptor antagonist AMD3100, glycogen synthase kinase-3 (GSK-3) inhibitors and histone deacetylase inhibitors (HDACi), that modulate the growth, differentiation and mobilization of SC, have been recently discovered and are currently under evaluation in both in vivo experimental models and preliminary clinical trials. Thus, modulation of SC properties through pharmacological treatment represents a new field of investigation which may lead to the development of novel strategies for the treatment not only of ischemic and degenerative disorders, but also of cancer.

Keywords: AMD3100, HDAC, GSK-3, statins, nitric oxide, Erythropoietin, glitazones, angiotensin-II receptor antagonists, ACE inhibitors, estrogens