Enabling stem cell therapies through synthetic stem cell-niche engineering

Abstract

Enabling stem cell-targeted therapies requires an understanding of how to create local microenvironments (niches) that stimulate endogenous stem cells or serve as a platform to receive and guide the integration of transplanted stem cells and their derivatives. In vivo, the stem cell niche is a complex and dynamic unit. Although components of the in vivo niche continue to be described for many stem cell systems, how these components interact to modulate stem cell fate is only beginning to be understood. Using the HSC niche as a model, we discuss here microscale engineering strategies capable of systematically examining and reconstructing individual niche components. Synthetic stem cell-niche engineering may form a new foundation for regenerative therapies.

Figure 1. The components of the HSC niche.

As a paradigm, a niche can be compartmentalized into signaling pathways activated by soluble cytokines either secreted as autocrine ligands by stem cells themselves or in a paracrine manner by niche support cells, cell-ECM/cell-substrate interactions, cell-cell contacts, mechanical forces, and systemic hormones and physicochemical cues. Examples are given here for components of the HSC niche. LFA1, lymphocyte function–associated antigen-1; PTH, parathyroid hormone; VLA4, very late antigen-4.

Figure 2. Dynamic interactions between HSCs and the niche.

In both the developing embryo (A) and the adult (B), HSC niches vary in time, location, and composition. The HSCs and their interactions with their current niche may provide the required signals to induce de novo hematopoiesis, maturation, or migration into the subsequent niche. In the adult, evidence suggests that HSCs reside in both endosteal and vascular niches that provide different molecular cues to regulate HSC quiescence and response to injury. There is still considerable controversy about the composition and role(s) of niche components and regulatory mechanisms active in the adult and embryonic HSC niches.

Figure 3. Strategies to engineer a stem cell niche.

There are a variety of approaches to engineer and control individual niche components. These strategies can be multiplexed to produce hybrid devices that simultaneously provide macroscopic (e.g., O₂-controlled bioreactors) and microscopic (e.g., micropatterned cocultures) control over the niche and stem cell fate. A poly(dimethyl siloxane) microfluidic device is shown (top right). hES cells were formed into 2,000-cell aggregates in 400-μm microwells (bottom right; scale bar: 100 μm). hES cells were immunostained with Hoechst 33342 (blue) and Oct-4 (green) on 400-μm Matrigel spots (bottom left; scale bar: 200 μm).

Figure 4. Engineering and modulating the niche in vivo.

This figure provides an overview of different clinically relevant strategies that may be used to manipulate the in vivo stem cell niche. Examples provided illustrate the molecular targeting of particular stem cell–niche interactions. CML, chronic myeloid leukemia; LSC, leukemic stem cell.