Artificial Hematopoietic Stem Cell Niches-Dimensionality Matters

Abstract

Hematopoietic stem cell niches are perhaps the best described niche system in mammals. The niches themselves, as well as their cellular and structural constituents and factors that play a role in maintaining the niche structure and function, are being refined on a more or less daily basis. Despite this, it seems as if the more we know the harder it gets to mimic the in vivo-situation using in vitro-systems. This is due to the fact that hematopoiesis is a multi step maturation process leading to HSC heterogeneity. Subpopulations of HSCs and niche supporting cells can be defined depending on characteristics such as their potency of leading to successful reconstitution of sub lethally irradiated mice in serial transplantation experiments or, with less scientific impact, clonogenic assays. Since the bone marrow obviously provides all necessary information to maintain the stem cell pool constant and to adapt the number of blood cells according to physiologic needs, it has been the goal to engineer artificial niches that display at least one or several of the major characteristics of the in vivosituation to make use of these systems for not only fundamental research purposes but, moreover, also for clinical applications. This review will give an overview of approaches to engineering artificial hematopoietic niches with a focus on the complexity/dimensionality of the systems used.

The extracellular matrix of hematopoietic stem cell niches

“…Many approaches have been used to improve HSC cultures by enabling interaction with ECM in vitro . The easiest way is to coat surfaces with ECM molecules, which enhances HSPC culture in comparison to simple suspension cultures without any directed possibility for cell–matrix interaction [522] . Such surface functionalization were conducted using full-length ECM proteins (e.g.…”

“…The next level of complexity is introduced by considering topography of the ECM and transferring cell cultures from a flat 2D system to “2.5D”. Microwell systems and nanofiber substrates are widely applied for this purpose as described above [454] , [486] , [512] , [522] , [523] , [524] .…”

“…Synthetic polymers often need to be further functionalized to allow efficient interactions with cells e.g. via adhesion [521] , [522] . Amongst the natural polymers, proteins such as collagen/gelatin or serum albumins as well as carbohydrates including chitosan, alginate, dextran, hyaluronic acid or heparin are applied [474] , [499] , [510] , [522] , [525] , [526] .…”

“…via adhesion [521] , [522] . Amongst the natural polymers, proteins such as collagen/gelatin or serum albumins as well as carbohydrates including chitosan, alginate, dextran, hyaluronic acid or heparin are applied [474] , [499] , [510] , [522] , [525] , [526] . More complex ECM mimics are provided by working with decellularized ECMs, derived either directly from bone or BM or from cell culture [522] , [527] , [528] , [529] , [530] .…”

“…Amongst the natural polymers, proteins such as collagen/gelatin or serum albumins as well as carbohydrates including chitosan, alginate, dextran, hyaluronic acid or heparin are applied [474] , [499] , [510] , [522] , [525] , [526] . More complex ECM mimics are provided by working with decellularized ECMs, derived either directly from bone or BM or from cell culture [522] , [527] , [528] , [529] , [530] . While they can preserve the natural composition and 3D architecture of the ECM, their composition is hardly ever exactly known, hampering the interpretation of results in terms of connecting observed cellular responses to a single ECM derived stimulus [525] .…”