In Vitro and In Vivo Modeling of Normal and Leukemic Bone Marrow Niches: Cellular Senescence Contribution to Leukemia Induction and Progression

Abstract

Cellular senescence is recognized as a dynamic process in which cells evolve and adapt in a context dependent manner; consequently, senescent cells can exert both beneficial and deleterious effects on their surroundings. Specifically, senescent mesenchymal stromal cells (MSC) in the bone marrow (BM) have been linked to the generation of a supporting microenvironment that enhances malignant cell survival. However, the study of MSC’s senescence role in leukemia development has been straitened not only by the availability of suitable models that faithfully reflect the structural complexity and biological diversity of the events triggered in the BM, but also by the lack of a universal, standardized method to measure senescence. Despite these constraints, two- and three dimensional in vitro models have been continuously improved in terms of cell culture techniques, support materials and analysis methods; in addition, research on animal models tends to focus on the development of techniques that allow tracking leukemic and senescent cells in the living organism, as well as to modify the available mice strains to generate individuals that mimic human BM characteristics. Here, we present the main advances in leukemic niche modeling, discussing advantages and limitations of the different systems, focusing on the contribution of senescent MSC to leukemia progression.

Temporary serine protease inhibition and the role of SPINK2 in human bone marrow

“…This difficulty can be overcome by the use of 3D tissue-engineered models of human bone marrow and by human hematopoietic xenotransplatation in mice. 65 , 66 , 67 Moreover, the TI-D theory can be applied to other members of the SPINK family and to other tissue contexts, thus ensuring a wider range of experimental conditions where to test its general validity.…”

The Molecular Context of Oxidant Stress Response in Cancer Establishes ALDH1A1 as a Critical Target: What This Means for Acute Myeloid Leukemia

“…At a later disease stage, loss of endothelial cells, osteoblasts, HSCs, and the suppression of normal hematopoiesis culminate in niche collapse [84]. AML causes senescence of stromal cells in the bone marrow microenvironment, and senescent mesenchymal cells increase the permissiveness of the bone marrow microenvironment for AML [85,86] (Figure 2).…”

Cellular Senescence in Physiological and Pathological Processes

“…Cellular senescence is also involved in cancer biology in a dual way: (i) by promoting protective anticancer mechanisms resulting in tumor growth arrest; (ii) or, paradoxically, by inducing cancer onset through the persistence of senescent cells in tissues. With regards to this topic, the review of Salazar-Terreros and Vernot gives an interesting hint about the effect of senescent cells in influencing the microenvironment which they live in [ 9 ]. The authors focused on the alteration of hematopoietic stem cells niche in bone marrow (BM) due to senescent mesenchymal stromal cells (MSCs), given MSCs are the major and relevant BM components.…”

“…The authors focused on the alteration of hematopoietic stem cells niche in bone marrow (BM) due to senescent mesenchymal stromal cells (MSCs), given MSCs are the major and relevant BM components. During aging, the phenotype and function of these cells change, triggering a senescent state that, in turn, impairs the cellular biology and aspects such as metabolism and secretome composition [ 9 , 10 , 11 ]. This could lead to a decrease in the immunomodulatory properties of MSCs and the promotion of proliferation and migration of leukemic cells [ 9 , 11 , 12 ].…”

“…During aging, the phenotype and function of these cells change, triggering a senescent state that, in turn, impairs the cellular biology and aspects such as metabolism and secretome composition [ 9 , 10 , 11 ]. This could lead to a decrease in the immunomodulatory properties of MSCs and the promotion of proliferation and migration of leukemic cells [ 9 , 11 , 12 ]. This could support a microenvironment enhancing malignant cell survival.…”