The human skeletal system plays a vital role in blood cell production because of the vast BM niches containing HSCs. These specific niches within the BM appropriately control HSC survival, self-renewal, migration, quiescence, and differentiation, which are directly attributed to the constant renewal of all the blood cell lineages. This paper examines the structure and many biological constituents in BM niches, including mesenchymal stem/stromal cells, endothelial cells, osteoblasts, megakaryocytes, macrophages, adipocytes, lymphoid cells, and nerve fibers. It also describes the complex relationship between those cellular elements and their ability to modulate the HSC function by secretion of various growth factors, cytokines, and chemokines.

The paper also examines the metabolism of HSCs within the niche. It stresses the importance of pathways like autophagy, fatty acid oxidation, glycolysis, and oxidative phosphorylation for controlling HSC quiescence, proliferation, or differentiation. Moreover, the investigation focuses on understanding the effects of niche aging and leukemic transformation on hematopoiesis, the possible changes that occur to the balance within the BM niches, and their effects on the production of red blood cells. The paper also considers iPSCs as a viable long-term solution for creating engraftable HSCs and the developmental programming of the hematopoietic system. Therefore, future therapeutic applications in this emerging field seem viable, especially in situations where conventional therapy options are limited. The paper also the current status of HSC niche modeling in vitro, which uses advanced methods, such as scRNA sequencing and mass cytometry, to understand the complex mechanisms of HSC interaction with the niche. Further research in this field will unveil the mentioned complexity of hematopoiesis, opening up new vistas for regenerative medicine and treatments that can change the existing picture of hematological diseases and abnormalities.

Key Words: Hematopoietic stem cells, bone marrow niche, hematopoiesis, quiescence, self-renewal, differentiation, glycolysis, oxidative phosphorylation, fatty acid oxidation, autophagy, induced pluripotent stem cells, leukemic transformation.

Introduction

Hematopoiesis, the synthesis of blood cellular components, occurs during embryonic development and throughout adulthood to produce and replenish the blood system (Kandarakov et al., 2022). Although HSCs are endowed with the capacity to renew the entire spectrum of blood cell lineages throughout life, all their operations are tightly controlled by specific structural and functional units in the BM called "niches" (Frisch, 2019). These niches, containing numerous cellular structures, growth factors, and ECM molecules, are critically essential to balance HSC self-renewal, quiescence, and differentiation.

Research interest in BM niches has increased in recent years due to the possibility of studying and possibly controlling stromal-cell regulated hematopoiesis for medical application. Therefore, the goals of this review are to discuss the function of the human skeletal system, particularly the BM niches, in the development of blood cells. These will include an understanding of the structure and cellular composition of these niches, the metabolic status and control of HSCs in their niches, and effects of aging and leukemic conversion of niche microenvironments on hematopoiesis. Moreover, it will elaborate on the developmental programming of the hematopoietic system and how iPSCs can be a reliable source for generation of engraftable HSCs.

Anatomy of Bone Marrow Niches

The BM can be viewed as a macro-niche for HSCs, while the distinct anatomical areas represent micro-niches that control HSC activity (Kandarakov et al., 2022). BM is a soft tissue found in the bone spaces, predominantly in the epiphysis and metaphysis of the long bones; this tissue harbors blood capillaries as well as stromal and hematopoietic cells.

Studies have demonstrated that HSCs reside in the hypoxic areas of the BM, with the peri-sinusoidal region considered the most hypoxic due to the lack of an arteriole; however, the endosteal regions are slightly less hypoxic as they are in closer proximity to the BM surface (Kandarakov et al., 2022, Frisch, 2019). Some works have established that HSC are situated in the halo of arterioles in the endosteal region (Kandarakov et al., 2022). However, other works have provided information that can be used to ascertain that HSC is related to sinusoidal blood vessels (Kandarakov et al., 2022; Frisch, 2019).

Cellular Components of Bone Marrow Niches

The following cellular elements are responsible for signaling to HSCs and regulating their activity:

Mesenchymal Stem/Stromal Cells (MSCs)

MSCs are also multipotent cells and play a crucial role in the support of HSCs through the synthesis of growth factors, cytokines, and chemokines, such as CXCL12, SCF, and VCAM-1 (Kandarakov et al., 2022; Zhao et al., 2020). There are different subsets of MSCs, such as Nes-GFP^bright^, NG2^+^, Nes-GFP^dim^, LEPR^+^, and CXCL12^high^ cells with different impacts on HSCs residing in different niches (Kandarakov et al., 2022).

Endothelial Cells (ECs)

Endothelial cells lining arterioles and sinusoids in BM including SCF, CXCL12, E-selectin, and NOTCH ligands also support HSC (Kandarakov et al., 2022; Frisch, 2019). These cells play a role in HSC quiescence, expansion, and migration/homing (Kandarakov et al., 2022; Frisch, 2019).

Osteoblasts

Positioned at the endosteal surface, osteoblasts are differentiated bone-forming cells, which, along with other components of the HSC niche, were identified earlier than many other bone marrow elements (Kandarakov et al., 2022). They have been implicated in the regulation of HSCs through the production of factors like TPO, angiopoietin-1, and osteopontin, as well as through the Notch signaling pathway (Kandarakov et al., 2022).

Megakaryocytes

Platelet-directing megakaryocytes have come to the forefront for their ability to control HSC cycling and lineage commitment. Some of these include CXCL4, TGFβ1, and TPO to regulate HSC quiescence and implication on their differentiation potential (Kandarakov et al., 2022).

Macrophages

BM microenvironments include BM macrophages that help to retain and control the position of HSCs in the niche. They promote HSC retention through interactions with Nes^+^ stromal cells and suppress HSC cycle entry through the TGFβ1/Smad signaling pathway (Kandarakov et al., 2022).

Adipocytes

Initially considered negative regulators of hematopoiesis, recent studies have revealed that adipocytes support HSC survival, proliferation, and differentiation through the production of factors like CXCL12, IL-8, CSF3, and LIF (Kandarakov et al., 2022). They also promote hematopoietic regeneration after stress conditions by producing SCF (Kandarakov et al., 2022).

Lymphoid Cells

Regulatory T cells (Tregs) have been found to co-localize with HSCs and protect them from immune attack within the niche, creating an immunologically privileged site (Kandarakov et al., 2022). Additionally, B cells, through the production of acetylcholine, have been shown to limit hematopoiesis (Kandarakov et al., 2022).

Nerve Fibers

The sympathetic and cholinergic nervous systems innervate the BM and regulate HSC mobilization and quiescence through the modulation of CXCL12 levels and other mechanisms (Kandarakov et al., 2022; Frisch, 2019).

Metabolism and Regulation of HSCs Within the Niche

The metabolic requirements of HSCs are tightly associated with their functions and affected by the niche. In the BM niches, quiescent HSCs are located in hypoxic areas, and they prefer glycolysis as their metabolic pathway rather than oxidative phosphorylation and ROS generation. This metabolic shift is regulated by such processes associated with Pdk, Meis1 and Hif -1α (Kandarakov et al., 2022).

When HSCs transition from a quiescent state to the active state and begin to proliferate and differentiate, oxidative phosphorylation and ROS production rise to meet energy demands (Kandarakov et al., 2022). Some of these include; CD36 mediated fatty acid uptake, Histone demethylase Fbxl10, and Mitochondrial carrier homolog 2 (MTCH2) (Kandarakov et al., 2022). In addition, p38MAPK, FAO, and autophagy pathways are essential for the metabolism and function of HSCs in the niche.

The p38MAPK signaling pathway with a focus on the p38α isoform, has been probed to play a role in the conversion of HSCs from G0 phase to S phase following hematopoietic stress. The phosphorylated form of p38α upregulates IMPDH2 in HSPCs to promote purine metabolism and enhance HSC proliferation and recovery (Kandarakov et al., 2022).

Another crucial metabolic pathway in HSC biology is fatty acid oxidation (FAO). The PML--PPAR-δ--FAO pathway regulates one-for-one division of HSCs, and its suppression results in one-for-one division and failure to maintain the HSCs (Kandarakov et al., 2022). Stimulation of the PPAR-δ–FAO pathway, resulting in mitophagy enhances HSC proliferation (Kandarakov et al., 2022). Another mitochondrial phosphatase related to PTEN is PTPMT1, which loss promotes the activation of the mitochondrial uncoupling protein 2 by fatty acids, expanding the population of primitive HSCs (Kandarakov et al., 2022).

For this reason, autophagy serves as a critical means through which HSCs can safeguard themselves against metabolic damage and remain quiescent and stem-like. Foxo3a is important for the non-sustained expression of autophagy in HSCs after prolonged starvation (Kandarakov et al., 2022). It was established that inhibition of autophagy in HSCs results in the buildup of mitochondria and an activated metabolism, promoting myeloid lineage commitment and the loss of stem cell function, which are hallmarks of an aging hematopoietic status (Kandarakov et al., 2022).

As mentioned before, HSCs metabolism is regulated by both intrinsic factors and factors of the cell microenvironment. For instance, MSCs, one of the key components of the HSC niche, are localized in regions of profound hypoxia within the BM and rely mainly on glycolysis as their major source of energy production (Kandarakov et al., 2022). This hypoxic environment is thought to play a role in maintaining the self-renewing MSC population and preventing their proliferation and aging (Kandarakov et al., 2022).

Moreover, there is growing evidence that mitochondria transfer between cells in the BM participate in the regulation of HSC function (Kandarakov et al., 2022). MSCs transfer their mitochondria to diverse cell types, including possibly HSCs, thus helping to recover the functions of HSCs carrying injured or depleted mitochondria.

Niche Aging and Leukemic Transformation

The non-transcriptional effects of aging and leukemic transformation can also affect the BM niches and their influence on HSCs. According to Kandarakov et al. (2022) during the life cycle of an individual, the niche cells and their ability to support hematopoiesis change, and this may negatively affect the stability of the system. Another consequence of aging is the gradual displacement of red marrow responsible for hematopoiesis by yellow fat marrow containing much fat (Kandarakov et al., 2022). This shift is associated with decreased hematopoietic activity and may be linked to the initial negative regulation attributed to adipocytes (Kandarakov et al., 2022). However, new studies have refuted these opinions, indicating that adipocytes can support hematopoietic regeneration in response to stress conditions (Kandarakov et al., 2022).

Leukemic transformation can also affect the BM niches to form a leukemic niche that supports survival and expansion of leukemic cells. This process can entail alteration of the cell identity, secretion of the soluble factors and alteration of the niche extracellular environment (Kandarakov et al., 2022). For instance, AML has been asserted to produce changes in the Non-Hematopoietic BM cellular composition in terms of adipogenesis and other osteolineage, (Kandarakov et al., 2022). It is necessary to understand the alterations of hematopoiesis, caused by niche ageing and leukemic conversion, for elucidating the curative measures that can help in creating and sustaining healthy hematopoiesis and in dealing with hematological malignancies.

Developmental Programming and Induced Pluripotent Stem Cells

The programming of the hematopoietic system development can be influenced by many factors, including parental adversity, fetal environment, and epigenetics (Balistreri et al., 2019). These early-life experiences and conditions alter the functionality of the hematopoietic system and predispose individuals to early aging and chronic diseases in adulthood (Balistreri et al., 2019).

A major area of interest is whether iPSCs could be used as a limitless source of engrafting HSCs. Although early efforts mainly recapitulated primary/secondary hematopoiesis with engrafting capacity, later work showed that iPSC-derived HSCs engraft through ectopic transcription factor expression (Demirci et al., 2020)

The derivation of patient-specific HSCs from iPSCs provides great promise in the management of malignant and nonmalignant hematologic diseases when other alternatives are not available (Demirci et al., 2020). Nevertheless, several hurdles remain for consideration, such as HSC development in later stages, identification of key signaling pathways, epigenetic modifications, and the effects of the HSC and iPSC niche on stem cell behavior and function (Demirci et al., 2020).

Conclusion

The human skeletal system is characterized by a complex system of bone marrow compartments, which is essential for human cell formation. These specialized compartments maintain the delicate balance between HSC proliferation, dormancy, and differentiation. To ensure the lifelong support of mature blood and immune cells. These encompass the structural and cellular components of the bone marrow niches, including mesenchymal stem/stromal cells, endothelial cells, osteoblasts, megakaryocytes, macrophages, adipocytes, lymphoid cells, and nerve fibers that regulate hematopoiesis. HSCs are strictly associated with the functions of the niche when the metabolic conditions of HSCs are hypoxic, glycolytic, oxidative phosphorylation, metabolic pathways FAO and autophagy. However, the BM niches may be modified by aging and leukemic transformation, which could impact their ability to accommodate and regulate HSCs. The design of targeted therapeutic interventions to maintain normal hematopoiesis and treat hematological malignancies is contingent upon an understanding of these processes.

Furthermore, the hematological system developmental programming and iPSC’s capacity to generate engraftable hematopoietic stem cells from a renewable source promises future therapeutic utilization, especially when faced with situations where conventional therapy options are limited. Therapy approaches and regenerative medicine may be expanded with this field of study as the details of how HSCs interact with their niche environments begin to be unveiled. This could radically transform the management of hematological diseases and disorders.