Heterocellular molecular contacts in the mammalian stem cell niche

Abstract

Adult tissue homeostasis and repair relies on prompt and appropriate intervention by tissue-specific adult stem cells (SCs). SCs have the ability to self-renew; upon appropriate stimulation, they proliferate and give rise to specialized cells. An array of environmental signals is important for maintenance of the SC pool and SC survival, behavior, and fate. Within this special microenvironment, commonly known as the stem cell niche (SCN), SC behavior and fate are regulated by soluble molecules and direct molecular contacts via adhesion molecules providing connections to local supporting cells and the extracellular matrix. Besides the extensively discussed array of soluble molecules, the expression of adhesion molecules and molecular contacts is another fundamental mechanism regulating niche occupancy and SC mobilization upon activation. Some adhesion molecules are differentially expressed and have tissue-specific consequences, likely reflecting the structural differences in niche composition and design, especially the presence or absence of a stromal counterpart. However, the distribution and identity of intercellular molecular contacts for adhesion and adhesion-mediated signaling within stromal and non-stromal SCN have not been thoroughly studied. This review highlights common details or significant differences in cell-to-cell contacts within representative stromal and non-stromal niches that could unveil new standpoints for stem cell biology and therapy.

Hematopoietic progenitors polarize in contact with bone marrow stromal cells by engaging CXCR4 receptors

“…Several pathways are involved in the physical interaction and biochemical crosstalk between hematopoietic progenitors and niche cells (Wilson and Trumpp, 2006) (Ceafalan et al, 2018). To identify those that were involved in the polarization of HSPC, we immunolabelled receptors known to play key roles in cell adhesion and the regulation of hematopoietic differentiation (Ceafalan et al, 2018), including the receptor pairings, VCAM-VLA4, ICAM-LFA1, and SDF1-CXCR4. All receptors appeared to be polarized and localized in the protrusion associated with the contact site of HSPC with the osteoblast ( Figure 5A).…”

“…It is interesting to consider that the polarization and anchoring we identified here ( Figure 5F) could be involved in the homing and tethering of HSPCs to a particular aspect of the bone-marrow niche. The centrosome polarization close to the contact site is reminiscent of the structure of immune (Stinchcombe et al, 2006) (Ritter et al, 2013) and of the polarization of several other types of stem cells with their niches (Ceafalan et al, 2018). Whether such polarization of the HSPC by CXCR4 leads to local exchange of signaling molecules (Gillette et al, 2009) and structural reorganization that regulates the quiescence and/or the asymmetry of subsequent HSPC divisions are interesting possibilities that deserve further investigations.…”

“…However the uropod is also involved in cell-cell interactions in T lymphocytes, (Sánchez-madrid and Serrador, 2009) and HSPCs (Wagner et al, 2008), suggesting that not only migration but also anchorage could involve HSPCs polarization. In support of this hypothesis, localized adhesion-associated signaling and exchange of endosomes between HSPCs and osteoblasts have suggested the existence of synapse-like interactions, as it is the case for many stem cells interacting with the cells forming their niche (Wilson and Trumpp, 2006) (Ceafalan et al, 2018) (Gillette et al, 2009). However, the cellular mechanism inducing the polarization of HSPCs in response to their adhesion to stromal cells has not yet been investigated in detail.…”

“…Within the bone-marrow, the vascular network and the bone matrix constitute local niches that impart distinct and specific signals regulating the quiescence, proliferation and differentiation of HSPCs (Morrison and Scadden, 2014) (Christodoulou et al, 2020) (Guezguez et al, 2013). Perturbed interactions between HSPCs and their niches have been associated with blood malignancies and ageing (Verovskaya et al, 2019), underscoring the importance of better understanding how HSPCs sense and respond to stromal and endothelial cells in the bone-marrow (Ceafalan et al, 2018).…”

“…Several lines of experimental evidence, in living organisms and in cultured cells have revealed that, in addition to diffusible signals, direct cell-to-cell contact is involved in the regulation of HSPC fate (Bruns et al, 2014) (Alakel et al, 2009) (Ceafalan et al, 2018) (Walenda et al, 2010). In co-cultures of human CD34+ HSPCs isolated from newborn cord blood and mesenchymal stromal cells from bone marrow aspirates , HSPCs can adopt elongated and asymmetric morphologies, with several types of protrusions of various length and width that can have specific impact on proliferation and differentiation (Freund et al, 2006) (Frimberger et al, 2001) (Holloway et al, 1999).…”