Heterogeneous stiffness of the bone marrow microenvironment regulates the fate decision of haematopoietic stem and progenitor cells.
Guolin ShiZhuo ChangPan ZhangXiaohang ZouXinmin ZhengXiru LiuJinxiao YanHuiyun XuZhenhao TianNu ZhangNing CuiLeming SunGuangkui XuHui YangPublished in: Cell proliferation (2024)
The bone marrow (BM) niches are the complex microenvironments that surround cells, providing various external stimuli to regulate a range of haematopoietic stem cell (HSC) behaviours. Recently, it has been proposed that the fate decision of HSCs is often correlated with significantly altered biophysical signals of BM niches. To thoroughly elucidate the effect of mechanical microenvironments on cell fates, we constructed 2D and 3D cell culture hydrogels using polyacrylamide to replicate the mechanical properties of heterogeneous sub-niches, including the inherent rigidity of marrow adipose tissue (2 kPa), perivascular tissue (8 kPa) and endosteum region (35 kPa) in BM. Our observations suggest that HSCs can respond to the mechanical heterogeneity of the BM microenvironment, exhibiting diversity in cell mechanics, haematopoietic pool maintenance and differentiated lineages. Hydrogels with higher stiffness promote the preservation of long-term repopulating HSCs (LT-HSCs), while those with lower stiffness support multi-potent progenitors (MPPs) viability in vitro. Furthermore, we established a comprehensive transcriptional profile of haematopoietic subpopulations to reflect the multipotency of haematopoietic stem and progenitor cells (HSPCs) that are modulated by niche-like stiffness. Our findings demonstrate that HSPCs exhibit completely distinct downstream differentiated preferences within hydrogel systems of varying stiffness. This highlights the crucial role of tissue-specific mechanical properties in HSC lineage decisions, which may provide innovative solutions to clinical challenges.
Keyphrases
- bone marrow
- stem cells
- single cell
- adipose tissue
- drug delivery
- cell therapy
- mesenchymal stem cells
- hyaluronic acid
- tissue engineering
- induced apoptosis
- decision making
- insulin resistance
- gene expression
- drug release
- cell cycle arrest
- high fat diet
- cell proliferation
- wastewater treatment
- skeletal muscle
- signaling pathway
- heat shock
- heat stress
- pi k akt