Dynamic Changes of the Bone Marrow Niche: Mesenchymal Stromal Cells and Their Progeny During Aging and Leukemia

Abstract

Mesenchymal stromal cells (MSCs) are a heterogenous cell population found in a wide range of tissues in the body, known for their nutrient-producing and immunomodulatory functions. In the bone marrow (BM), these MSCs are critical for the regulation of hematopoietic stem cells (HSC) that are responsible for daily blood production and functional immunity throughout an entire organism’s lifespan. Alongside other stromal cells, MSCs form a specialized microenvironment BM tissue called “niche” that tightly controls HSC self-renewal and differentiation. In addition, MSCs are crucial players in maintaining bone integrity and supply of hormonal nutrients due to their capacity to differentiate into osteoblasts and adipocytes which also contribute to cellular composition of the BM niche. However, MSCs are known to encompass a large heterogenous cell population that remains elusive and poorly defined. In this review, we focus on deciphering the BM-MSC biology through recent advances in single-cell identification of hierarchical subsets with distinct functionalities and transcriptional profiles. We also discuss the contribution of MSCs and their osteo-adipo progeny in modulating the complex direct cell-to-cell or indirect soluble factors-mediated interactions of the BM HSC niche during homeostasis, aging and myeloid malignancies. Lastly, we examine the therapeutic potential of MSCs for rejuvenation and anti-tumor remedy in clinical settings.

Tumor Microenvironment in Acute Myeloid Leukemia: Adjusting Niches

“…The underlying change of MSC differentiation is achieved via different mechanisms, including altered cytokine levels, resulting in decreased Wnt-related signaling and intensified RhoA-related signaling ( 38 ) as well as reduced Runx2 signaling, which is important for osteoblastic differentiation ( 39 ). “Senescence” that can be attributed to (cumulative effects of) pro-inflammatory cytokines, and changes of the sympathetic nerve system during life affect MSC ( 40 ). Indeed and as a cumulative result of altered signaling in cancer, nestin-positive MCS are significantly reduced in several hematologic malignancies.…”

Bone Marrow Aging and the Leukaemia-Induced Senescence of Mesenchymal Stem/Stromal Cells: Exploring Similarities

“…As mentioned above, haematopoietic niches are composed of diverse types of cells, of which MSCs, in spite of their heterogeneity [ 9 , 11 , 57 ], have acquired much attention due to their capacity to differentiate into mesenchymal lineages (osteoblasts, chondroblasts, and adipocytes), to stimulate bone growth and remodelling, and their ability to support haematopoiesis [ 58 , 59 ]. Confirming their capability to support and maintain HSC properties, MSCs are capable of ectopically organizing HSC niches with fully functional haematopoiesis [ 58 ].…”

“…Aging of the BM is believed to be the cause of the increased incidence of haematological malignancies in the elderly, and this can be envisaged as a result of both age-associated haematopoietic stem cell (HSC) dysfunction [ 8 ] and the particular altered characteristics and functions of aging stromal cells building a permissive milieu where leukaemia can be established and developed [ 9 ]. There is already abundant evidence showing that leukemic cell growth induces important alterations in the bone marrow (BM) microenvironment and, in turn, this remodelled BM has important roles in leukaemia maintenance, protection, progression, drug resistance, and relapse [ 9 , 10 , 11 , 12 ]. Since haematological malignancies have different cells of origin, diverse genetic abnormalities and also present distinctive clinical manifestations, one would imagine that the interaction with the BM microenvironment (and their modifications) might be specific to a particular leukaemia subtype.…”

Recent Advances in Single-Cell View of Mesenchymal Stem Cell in Osteogenesis

“…As the source of cells in bone marrow, MSC maintains bone metabolism. However, with the increase of age, MSCs tend to differentiate into adipocytes and decreased osteogenesis, leading to an increased risk of aging-related bone diseases for the elderly, and taking a long time to heal fractures ( Woods and Guezguez, 2021 ). Experiments have shown that senescent MSCs exhibit reduced clonal formation and proliferation capabilities compared to young donor-derived MSCs in vivo and lineage tracing in vitro demonstrated an age-dependent lineage transition between osteogenesis and adipogenic differentiation ( Sui et al, 2020 ).…”