β3-Adrenoreceptors as ROS Balancer in Hematopoietic Stem Cell Transplantation

In the last decades, the therapeutic potential of hematopoietic stem cell transplantation (HSCT) has acquired a primary role in the management of a broad spectrum of diseases including cancer, hematologic conditions, immune system dysregulations, and inborn errors of metabolism. The different types of HSCT, autologous and allogeneic, include risks of severe complications including acute and chronic graft-versus-host disease (GvHD) complications, hepatic veno-occlusive disease, lung injury, and infections. Despite being a dangerous procedure, it improved patient survival. Hence, its use was extended to treat autoimmune diseases, metabolic disorders, malignant infantile disorders, and hereditary skeletal dysplasia. HSCT is performed to restore or treat various congenital conditions in which immunologic functions are compromised, for instance, by chemo- and radiotherapy, and involves the administration of hematopoietic stem cells (HSCs) in patients with depleted or dysfunctional bone marrow (BM). Since HSCs biology is tightly regulated by oxidative stress (OS), the control of reactive oxygen species (ROS) levels is important to maintain their self-renewal capacity. In quiescent HSCs, low ROS levels are essential for stemness maintenance; however, physiological ROS levels promote HSC proliferation and differentiation. High ROS levels are mainly involved in short-term repopulation, whereas low ROS levels are associated with long-term repopulating ability. In this review, we aim summarize the current state of knowledge about the role of β3-adrenoreceptors (β3-ARs) in regulating HSCs redox homeostasis. β3-ARs play a major role in regulating stromal cell differentiation, and the antagonist SR59230A promotes differentiation of different progenitor cells in hematopoietic tumors, suggesting that β3-ARs agonism and antagonism could be exploited for clinical benefit

Inside the Biology of the β3-Adrenoceptor

Since the first discovery in 1989, the β3-adrenoceptor (β3-AR) has gained great attention because it showed the ability to regulate many physiologic and metabolic activities, such as thermogenesis and lipolysis in brown and white adipose tissue, respectively (BAT, WAT), negative inotropic effects in cardiomyocytes, and relaxation of the blood vessels and the urinary bladder. The β3-AR has been suggested as a potential target for cancer treatment, both in adult and pediatric tumors, since under hypoxia its upregulation in the tumor microenvironment (TME) regulates stromal cell differentiation, tumor growth and metastases, signifying that its agonism/antagonism could be useful for clinical benefits. Promising results in cancer research have proposed the β3-AR being targeted for the treatment of many conditions, with some drugs, at present, undergoing phase II and III clinical trials. In this review, we report the scientific journey followed by the research from the β3-Ars’ discovery, with focus on the β3-Ars’ role in cancer initiation and progression that elects it an intriguing target for novel antineoplastic approaches. The overview highlights the great potential of the β3-AR, both in physiologic and pathologic conditions, with the intention to display the possible benefits of β3-AR modulation in cancer reality