The Role of Heme Oxygenase-1 in Hematopoietic System and Its
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Cellular and Molecular Life Sciences https://doi.org/10.1007/s00018-021-03803-z Cellular andMolecular Life Sciences REVIEW The role of heme oxygenase‑1 in hematopoietic system and its microenvironment Agata Szade1 · Krzysztof Szade1 · Mahdi Mahdi1 · Alicja Józkowicz1 Received: 13 October 2020 / Revised: 9 February 2021 / Accepted: 24 February 2021 © The Author(s) 2021 Abstract Hematopoietic system transports all necessary nutrients to the whole organism and provides the immunological protection. Blood cells have high turnover, therefore, this system must be dynamically controlled and must have broad regeneration potential. In this review, we summarize how this complex system is regulated by the heme oxygenase-1 (HO-1)—an enzyme, which degrades heme to biliverdin, ferrous ion and carbon monoxide. First, we discuss how HO-1 infuences hematopoietic stem cells (HSC) self-renewal, aging and diferentiation. We also describe a critical role of HO-1 in endothelial cells and mesenchymal stromal cells that constitute the specialized bone marrow niche of HSC. We further discuss the molecular and cellular mechanisms by which HO-1 modulates innate and adaptive immune responses. Finally, we highlight how modulation of HO-1 activity regulates the mobilization of bone marrow hematopoietic cells to peripheral blood. We critically discuss the issue of metalloporphyrins, commonly used pharmacological modulators of HO-1 activity, and raise the issue of their important HO-1-independent activities. Keywords HO-1 · Hmox1 · HSPC · Hematopoiesis · Niche Introduction self-renew over the entire lifetime, what is progressively lost as they diferentiate toward ST-HSC and MPP. MPP diferen- HSC and their niche, hematopoiesis tiate downstream into two types of oligopotent progenitors: common myeloid progenitors (CMP) and common lymphoid Hematopoietic stem cells (HSC) produce all the blood cells progenitors (CLP), where myeloid oligopotent progenitors throughout life in a process called hematopoiesis. The main will give rise to bipotent megakaryocyte-erythrocyte pro- characteristics of HSC are self-renewal and diferentiation genitors (MEP) and granulocyte–macrophage progenitors toward all cells among the hematopoietic blood lineages (GMP) [5, 6]. Those oligopotent progenitors will eventu- (reviewed in [1, 2]). ally diferentiate to unipotent progenitors and ultimately The rare HSC sit at the apex of the hierarchical structure will give rise to downstream diverse mature progenies [7]. of the hematopoietic system. In 1988 Weissman laboratory Several studies based on single-cell transplantation assays isolated murine HSC and showed that this cell population questioned, however, the classic hematopoietic hierarchical diferentiates to all mature blood lineages in the irradiated diferentiation tree and suggested that subpopulation of HSC mice [3]. Further research revealed three distinct subpop- may directly diferentiate to lineage-biased progenitors, skip- ulations at the top of hematopoietic tree: long-term HSC ping the MPP stage [8, 9]. (LT-HSC), short-term HSC (ST-HSC), and multipotent The proper function of HSC tightly depends on the bone progenitors (MPP) [4]. While all of these populations have marrow (BM) microenvironment named ’niche’. This spe- multipotent diferentiation potential, only the LT-HSC can cialized niche sustains the multipotency and self-renewal of HSC and prevents their exhaustion. Therefore, the niche is critical for maintaining the hematopoietic homeostasis and * Agata Szade [email protected] regulating the response of hematopoietic system in stress conditions [10]. 1 Department of Medical Biotechnology, Faculty The conceptualization of stem cell ’niche’ as a special- of Biochemistry, Biophysics and Biotechnology, Jagiellonian ized microenvironment within the BM referred to studies University, Gronostajowa 7, 30-387 Krakow, Poland Vol.:(0123456789)1 3 A. Szade et al. done a few decades earlier by Schofeld (1978). He pro- the HSC-niche interaction within the BM and their function posed that the niche regulates HSC properties of multi- are incompletely understood. potency, self-renewal, and quiescence via specifc signals The existence of clonal precursors for hematopoiesis [11]. Over the years this concept was consequently con- was suggested already in 1960′s [26, 27] and since then frmed by numerous studies that demonstrated many cel- HSC became one of the most intensively studied subjects lular and non-cellular components of the HSC-niche. The of research. Nevertheless, there are still a lot of unanswered niche complex milieu provides the HSC with the essential questions and controversies concerning their biology and physical interaction and the molecular cues that are criti- diferentiation and their interactions with their niche [28]. cal for the diferentiation, maintenance, and localization Among many factors that were shown to regulate this system of HSC. was heme oxygenase-1 (HO-1). HSC niche is composed of several cell types. First fnd- ings showed a crucial role of stromal cells, and identifed Heme oxygenase‑1 clonal BM stromal cells which support the HSC self- renewal, and the maturation of both CMP and CLP [12]. Heme oxygenase is an enzyme which degrades heme [29]. Of diferent mesenchymal stromal cells (MSC), CXCL12- The products of the reaction catalyzed by heme oxygenase abundant reticular (CAR) cells are essential for maintaining are equimolar amounts of carbon monoxide (CO), ferrous the quiescence of HSC [13]. CAR phenotype highly over- ions and biliverdin, which is subsequently converted to bili- laps with the later-described leptin receptor-expressing MSC rubin by biliverdin reductase (BVR) [30]. Catalytic heme (LepR +) [14]. While it was initially indicated that HSC degradation requires an electron donor, that is NADPH pro- niche locates near the endosteum [15, 16], further studies vided by P450 cytochrome reductase and oxygen (reviewed suggested that the majority of HSC reside in direct proxim- in [31], (Fig. 1)). ity of blood vessels rather than near bone surface [17–19]. There are two existing isoforms of heme oxygenase, The development of the transgenic mouse models and HO-1 and HO-2 [32, 33], encoded by two diferent genes, advanced microscopy techniques facilitated the identi- HMOX1 and HMOX2 [31]. While HO-2 is a constitutive fcation of subsequent cellular elements of HSC niche as isoform, expressed mainly in the brain and testes [34, 35], essential factors in regulating HSC function. These included HO-1 is induced by a variety of factors. The most obvious hematopoietic cell types such as megakaryocytes [20], and advantage of HO-1 activity is the removal of free heme, non-hematopoietic cell types such as MSC, adipocytes and which is a known pro-oxidant, and a direct regulator of sev- glial cells, as well as niche-derived growth factors and sign- eral transcription factors [36]. Moreover, heme can act as a aling molecules, along with their receptors [21, 22]. damage-associated molecular pattern (DAMP) and activate HSC progenies are also able to regulate HSC activities in innate immune response [37]. a feedback loop. For instance, HSC quiescence can be regu- Of all the heme degradation products, CO seems to be lated directly by megakaryocytes [20, 23–25]. Bruns et al. the most important in the regulation of the immune system described HSC subpopulation associated with megakaryo- (reviewed in [31]). CO reduces the production of proin- cytes, and reported that depletion of megakaryocytes may fammatory cytokines—IL (interleukin)-1, IL-6, TNFα trigger HSC proliferation [23]. After exposure to a lethal (tumor necrosis factor α) and the expression of adhesion dose of radiation, megakaryocytes drive the repair of HSC molecules, and simultaneously increases the production of niche via osteolineage cell diferentiation [24]. anti-infammatory IL-10 [38]. CO afects the transmission Despite the extensive studies on HSC niche, some ques- of signals from certain TLRs (Toll-like receptors), which tions are still unanswered and some mechanisms underlying are very important in the initiation of immune responses Fig. 1 Catalytic reaction of immunomodulatory heme oxygenase (HO-1 and antiproliferative HO-2). Heme is degraded into antiapoptotic + NADPH CO, Fe2 and biliverdin. The + reaction requires molecular oxy- CO 3O gen and NADPH. Water-soluble 2 + biliverdin is further reduced to HO-1 BVR insoluble bilirubin by biliverdin heme biliverdin bilirubin reductase (BVR) HO-2 proinflammatory 2+ Fe antioxidant pro-oxidative ferritinsynthesis: anti-inflammatory antiapoptotic 1 3 The role of heme oxygenase-1 in hematopoietic system and its microenvironment against pathogens [39]. CO can also act as an anti-apop- sclerosis [62], chemotherapy-induced neutropenia [63] and totic factor by modulating Fas/Fas ligand and Bcl-2 family cardiovascular diseases [64, 65]. [40]. The second of the heme degradation products, biliver- din, is almost instantly converted to bilirubin by BVR [41]. Role of HO‑1 in HSC and progenitors Bilirubin is a potent antioxidant and anti-infammatory fac- tor—it is an efcient scavenger of reactive oxygen species Due to the anti-infammatory, antioxidative and anti-apop- [42] and inhibits the adhesion molecules signaling [43, 44]. totic properties of HO-1, it was hypothesized that HO-1 The last of the HO-1 reaction products, ferrous ions, can interferes with the HSC diferentiation. The role of HO-1 be considered harmful. However, the release of potentially in steady-state regulation of HSC is supported by our study pro-oxidant