MICROENVIRONMENTAL CONTROL OF HEMATOPOIETIC STEM CELLS: IMPLICATIONS FOR REGENERATION AND THERAPY

Abstract

The hematopoietic stem cells are concentrated in localized bone-marrow micro-environmental niches that tightly regulate the balance between quiescence, self-renewal as well as differentiation. This review systematically covers the complicated biological and physical determinants of hematopoietic stem cell fate. First, we discuss the most significant input of physical and mechanical signals, including stiffness of the extracellular matrix and sheer force of blood flows, along with the high level of spatial heterogeneity of the endosteal and perivascular compartments. Besides, we highlight the high impact of the critical chemical signals, such as metabolic programming, cytokines and trophic factors that interact in a synergistic manner with cellular interactions, which are mediated by mesenchymal stromal cells, osteoblasts, and immune constituents. The fundamentals of molecular pathways that are central, especially the Notch and Wnt signaling and their influence on the epigenome are outlined to demonstrate the processes through which the hemopoietic stem cell respond to the environmental stimuli. Most importantly this review mentions pathological perturbation of the niche which contrasts both the inflammatory degradation that accompanies the aging microenvironment termed inflammaging and the subverted, protective milieu found in leukemic niches. Finally, a wrap up on the combination of the basic biology with the translational therapies is also provided and this gives an overview of new developments in the field of bioengineered scaffold and microfluidic bioreactors and niche-specific agents like CXCR4 antagonists. Through explaining the interaction between these complex micro-environmental factors, it can be assumed that future studies can optimize personalized niche modeling, scale up ex-vivo stem-cell growth, and develop next-generation precision therapy to blood diseases.