Challenges and Opportunities to Harnessing the (Hematopoietic) Stem Cell Niche

Abstract

In our body, stem cells reside in a microenvironment termed the niche. While the exact composition and therefore the level of complexity of a stem cell niche can vary significantly tissue-to-tissue, the stem cell niche microenvironment is dynamic, typically containing spatial and temporal variations in both cellular, extracellular matrix, and biomolecular components. This complex flow of secreted or bound biomolecules, cytokines, extracellular matrix components, and cellular constituents all contribute to the regulation of stem cell fate specification events, making engineering approaches at the nano- and micro-scale of particular interest for creating an artificial niche environment in vitro. Recent advances in fabrication approaches have enabled biomedical researchers to capture and recreate the complexity of stem cell niche microenvironments in vitro. Such engineered platforms show promise as a means to enhance our understanding of the mechanisms underlying niche-mediated stem cell regulation as well as offer opportunities to precisely control stem cell expansion and differentiation events for clinical applications. While these principles generally apply to all adult stem cells and niches, in this review, we focus on recent developments in engineering synthetic niche microenvironments for one of the best-characterized stem cell populations, hematopoietic stem cells (HSC). Specifically, we highlight recent advances in platforms designed to facilitate the extrinsic control of HSC fate decisions.

Marrow-inspired matrix cues rapidly affect early fate decisions of hematopoietic stem and progenitor cells

“…The explicit role matrix ligands play in modulating HSC fate decisions has remained largely unknown because of the complexity of the matrix surrounding HSCs in vivo ( 22 , 39 ). Previous reports have suggested that ECM components, such as matrix proteins (for example, fibronectin, collagen, laminin, and osteopontin) and proteoglycans, may affect hematopoiesis and HSC function in vivo; further, matrix proteins, such as fibronectin and collagen, have been shown to induce adhesion-mediated morphological changes in HSCs in vitro ( 22 , 39 ).…”

Engineering a Cell Home for Stem Cell Homing and Accommodation

“…With entering the 21st century, artificial 3D culture environments have greatly improved with respect to their efficiency, versatility and robustness, hence providing dynamic systems with the ability to address many, if not all, fundamental questions about biomaterial regulation of live stem cell fate and function . Of particular interest, recent advances in fabrication approaches at the micro‐ and nanoscale have allowed biomedical scientists to capture and engineer the complexity and repertoire of the ECM in 3D cell culture platforms with complex flow of ECM components, cellular constituents, and secreted or bound biomolecules and cytokines in vitro …”

“…However, if the aim is the generation of tissue‐ and organ‐like structures for reconstructive purpose, higher complexity levels of biomaterial systems (such as in vitro 3D culture models and in situ biosensing tools) presenting physicochemical and biological cues in a temporospatial manner are absolutely justified . We expect that the future 3D tools and systems will be capable of inducing tissue‐specific cell differentiation, modulating cell geometry and monitoring cellular responses, among others; generate new insights into fundamental cellular behavior information; and lead to more and more biomedical applications ranging from 3D cell culture and production, stem cell therapy, and tissue engineering to drug discovery and development …”

A synthetic, three-dimensional bone marrow hydrogel

“…Prior to cleavage, the solution was diluted to 2 M urea with 100 mM ammonium bicarbonate at pH 8. Proteins were cleaved via trypsin (Thermo) and Lys-C endoproteinase (Promega, Madison, WI), at a ratio of 1:50 enzyme to protein overnight (12)(13)(14)(15)(16) hours) at 37°C. Samples were cleaned and concentrated using a C18 column (Thermo).…”

“…For example, protein composition and tissue stiffness are important for cellular processes like migration and proliferation 7,89 , as well as regulating stem cell fate and organoid development [10][11][12] . Thus, it is not surprising that the surrounding extracellular matrix (ECM) plays a key role in the proper function of bone marrow because both hematopoietic and stromal progenitor cells originate from this tissue 13 . For example, both bone marrow stiffness and fibronectin are important for the maintenance of hematopoietic stem cell progenitors 14 .…”