Aging of the Hematopoietic Stem Cell Niche: New Tools to Answer an Old Question

Abstract

The hematopoietic stem cell (HSC) niche is a specialized microenvironment, where a complex and dynamic network of interactions across multiple cell types regulates HSC function. During the last years, it became progressively clearer that changes in the HSC niche are responsible for specific alterations of HSC behavior. The aging of the bone marrow (BM) microenvironment has been shown to critically contribute to the decline in HSC function over time. Interestingly, while upon aging some niche structures within the BM are degenerated and negatively affect HSC functionality, other niche cells and specific signals are preserved and essential to retaining HSC function and regenerative capacity. These new findings on the role of the aging BM niche critically depend on the implementation of new technical tools, developed thanks to transdisciplinary approaches, which bring together different scientific fields. For example, the development of specific mouse models in addition to coculture systems, new 3D-imaging tools, ossicles, and ex-vivo BM mimicking systems is highlighting the importance of new technologies to unravel the complexity of the BM niche on aging. Of note, an exponential impact in the understanding of this biological system has been recently brought by single-cell sequencing techniques, spatial transcriptomics, and implementation of artificial intelligence and deep learning approaches to data analysis and integration. This review focuses on how the aging of the BM niche affects HSCs and on the new tools to investigate the specific alterations occurring in the BM upon aging. All these new advances in the understanding of the BM niche and its regulatory function on HSCs have the potential to lead to novel therapeutical approaches to preserve HSC function upon aging and disease.

Endothelial Senescence and the Chronic Vascular Diseases: Challenges and Therapeutic Opportunities in Atherosclerosis

“…In this regard, recent studies suggest that this process could be related to dysfunctional hematopoiesis, named clonal hematopoiesis (CH) of indeterminate potential (CHIP). In CHIP, the inflammatory environment in the bone marrow led to the generation of malignant clones and inflammation [55][56][57].…”

Increasing Complexity of Molecular Landscapes in Human Hematopoietic Stem and Progenitor Cells during Development and Aging

“…Although not the focus of this manuscript, alterations in the aged bone marrow microenvironment (e.g., in stromal and immune cells, cytokine/chemokine/extracellular matrix production and inflamm-aging) may lead to changes (e.g., of location, regulation, function) in HSPCs and support their evolution to hematological malignancies. The studies, which support these conclusions [ 19 , 250 , 273 , 274 , 275 , 276 , 277 ], are not reiterated here, except to highlight the controversy that surrounds the clonal origin of MDS MSC and MDS associated gene mutations or chromosomal rearrangements in MSCs that contribute to MDS progression, and which are described in detail in recent reviews [ 250 , 278 , 279 ]. Initial experiments in mice demonstrated that disruption of hematopoiesis associated with progression to an MDS-like disorder (characterized by anemia, thrombocytopenia, reduced B lymphoid cells and increased myeloid cells) occurred when the Dicer1 gene was deleted in murine osteoprogenitor cells [ 280 ].…”

“…Here and with these inherent biases in mind, we review recent molecular advances in single-cell (sc) omics analyses of human HSPCs, set against huge historical efforts spanning more than five decades that have aimed to identify and characterize human HSCs, their lineage-committed progeny during development and aging, and that provide mechanistic insights. Additional sophisticated technological advances over these decades include the discovery of monoclonal antibodies, the development of flow cytometry and cell sorting, of enhanced in situ imaging and single-cell capture technologies for the immunophenotypic identification and isolation of specific human HSPC subsets, of single-cell barcoding, lineage tracing, fate mapping and gene editing, and of sophisticated gene regulatory and three-dimensional genome organizational analyses, coupled with surrogate models in vivo and/or in vitro to assess the function of HSCs and their progeny, or following transplantation into human recipients as exemplified in some of our own and other studies [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ]. Not only have these approaches provided insights into human hematopoiesis during development and aging, but they have also identified significant heterogeneity in HSCs and their progeny, led to newer concepts of lineage commitment and differentiation, and contributed to an understanding of the cell of origin for hematological disorders and diseases.…”

Functionalized 3D scaffolds for engineering the hematopoietic niche

“…The topography provides regulatory signals toward different cellular outcomes and the BM is influenced by the ECM ( Jiang and Papoutsakis, 2013 ; Liu et al, 2022 ). The secreted ECM is mainly composed of structural proteins such as collagen I and IV, glycoproteins like fibronectin and laminin, and glycosaminoglycans (GAGs) ( Matteini et al, 2021 ). The matrix organization varies within the niche showing a higher concentration of fibronectin and collagen type IV in the endosteal zone and a higher presence of laminin and collagen I in the perivascular region ( Choi et al, 2015 ).…”