Essay topic 1: stem cell niche part 2 Flashcards
Epidermal stem cell niche?
Adult epidermal stem cells reside in specific stem cell niches, which play essential functions in regulating stem cell proliferation in order to maintain the epidermis homeostasis, and in protecting stem cells from depletion and undesirable stimuli [5]. Cell-cell and cell-ECM communication within the niche maintains stem cells in undifferentiated state or promote their differentiation. At least three epidermal stem cell niches have been found in the skin: the basal layer of interfollicular epidermis (IFE), hair follicle (HF) bulge, and the base of the sebaceous gland [6,7,8,9] The main components of epidermal BM are fibrous forming proteins (type IV and VII collagens, elastin), glycoproteins (laminin, fibronectin), nidogen, and proteoglycans (heparin sulfate, perlecan) While many ECM components are similar across different tissues, even within specific regions of the skin and at different developmental stages, there is considerable anatomical and molecular variation in their expression [75]. For example, laminins and integrins show heterogeneity in different regions of the skin BM [76,77]. Such variation in BM components and integrin expression provides many distinct cell adhesive properties and may potentially create an environment that is appropriate for stem cell maintenance. Laser ablation studies show that if a stem cell is removed, another nearby cell (even a progenitor) can replace it, proving the niche’s role in regeneration……… chermnykh et al (2018)
in the mammalian epidermis wnt signalling has a complex role in the differentiation of hair follicle precursors rather than self renewal of the multipotent stem cells in the follicular bulge. excessive activation of wnt signalling can accelerate the hair cycle and promote the growth of new follicles eventually leading to skin tumours. Wnt/β-catenin signaling is well recognized to play a role in controlling epidermal stem cell maintenance and fate decision. It participates in multiple processes in the skin, including cell-matrix interactions within the niche and outside…….
Mechanical forces originating from the differentiated epidermis and dermis indirectly influence the fate of EpSCs. It has been shown that increased contractility in the upper layers can induce intra-tissue tension, stimulating EpSC proliferation while inhibiting their differentiation and migration [57]. us. Overall, compression and tensile stress exert contrasting effects on EpSCs: compression typically causes depletion and suppressed division, while stretching promotes proliferation and hair regeneration. (Tang et al 2024)
Haematopoietic stem cell niche?
in addition to secreted protein factors, small molecules and ions can provide important signals in stem cell niches. in the o=bone marrow, high local ca2+ concentrations facillitate the localisation of HSCs adjacent to osteoblasts at the endosteum. the hypoxic microenvironment of HSCs niches in the bone may be important to limit the exposure of HSCs to reactive oxygen species which appear to induce an oxidative stress response that leads to HSC dysfunction. cadherin-mediated cell adhesion has been suggested to facillitate HSC association with osteoblasts (through N cadherin). high levels of beta1 integrin appear to be characteristic of blood-forming HSCs in the bone marrow. adhesion receptors in the blood system including membrane-bound steel factor (SLF), c-kit and CXCR4 appear to mediate HSC retention in the niche. Populations like HSCs encounter multiple niches throughout development that could be customised to support symmetric versus assymetric divisions to facilitate rapid proliferation or impose stem cell quiscence or to bias differentiation of progenitor cells towards one particular lineage. notch signalling has been found to promote osteogenic differentiation of mscs.
Manipulation of stem cell niche in vivo?
over the last years, a variety of 3D cell culture systems in stem cell biology has been developed. Such 3D models provide excellent in vitro tools to study cellular responses replicating in vivo environment [122]. 3D cultivation system demonstrated the maintenance of limbal epithelial stem cells [123] and gastric stem or progenitor cells within the stem cell niche over the long term without addition of special reagents [124]. To replicate the basic skin system, organotypic cocultures were developed based on type I collagen matrix inhabited by fibroblasts and keratinocytes. In this 3D coculture system, a normal epidermal phenotype and BM membrane structure could be reconstructed [125,126]. Using of natural ECM proteins as scaffold resemble the native in vivo environment cells are exposed in, bioengineered synthetic scaffolds may exhibit any required mechanical and physical characteristics mimicking the in vivo stem cell niche [127]. chermnykh et al (2018) While in vitro cultures FACS-purified LRG5+ cells give rise to organoids known as mini-guts.
Manipulation of stem cell niche in vitro?
Matrix properties can be replicated exquisitely recapitulated in vitro. many different types of secreted matrix can be purified and used for cell culture .
Scientists can purify secreted ECM components (like fibronectin, collagen, or laminin) and use them to grow cells.
ECM components can be assembled into microarrays—small-scale experiments where different matrix compositions are tested to see how cells react.
Technological strategies to control the cellular environment in vitro
Patterning ligands on substrates: Arranging proteins in 2D/3D patterns to control cell adhesion and signaling.
Controlling rheological properties: Using materials like hydrogels (which mimic the stiffness of tissues) or mechanical transducers (devices that apply forces to cells) to study how mechanical properties affect cells.
Presenting topographical features: Creating nano-scale textures, fibril structures, or geometric confinement to study how cell shape and movement are affected.
Modulating space and time variations: Using gradients of soluble factors or making the ECM properties change over time to mimic dynamic conditions in the body.
Model of niche dysfunction in epithelial cancer progression?
during normal homeostasis or injury-induced regeneration, the stromal niche supplies both proliferative and differentiative signals to the overlying epitheli,
during the early stages of cancer formation, genetic lesions with intrinsic proliferative effects in nascent tumour cells obviate the need for proliferative signals from the stromal niche. at this early stage however, differentiation-promoting factors from the stromal niche are still able to restrain tumour growth/invasion.
over time, modifications of stromal niche by tumour cells disrupts production of differentiation-inducing factors allowing unrestrained cancer invasion and progression.
Hierarchical model of carcinogenesis?
normal stem cells have limited proliferative capacity and give rise to progenitor cells that proliferate and differentiate into various types of cells. if a normal cell escapes regulation it becomesa a cancer stem cell (CSC) which can self renew and produce cancer progenitor cell. cancer progenitor cells give rise to poorly differentiated cells and they might form different subtypes of tumours with limited proliferative capacity. due to plasticity the cancer progenitor cells can de differentiate to become cscs. either cscs from normal stem cells or from cancer progenitor cells initiate and sustain aggressive tumour growth and the cells of origin for these 2 types of tumours are either cscs or cancer progenitor cells respectivley.
Stochastic model of carcinogenesis?
healthy epithelial cells develop an oncogenic mutation that forms hyperplasia. some of the hyperplastic cells become the cells-of-origin developing additional oncogenic mutations and transform into tumour cells. under multiple clonal evolutions aggressive tumours can form. some mutations can ;ead to a stem cell like permissive epigenome and create cancer progenitor cells. this process reconciles the stochastic model with the hirearchal model. however, if the hyperplastic cells develop non-oncogenic mutations they will not transform into tumour cells although they may continue to proliferate. if healthy epithelial cells initially undergo non-oncogenic mutations, they can overcome such maintain a healthy tissue.
Cancer stem cells?
cscs are cancer cells that can self-renew. their plasticity and dormancy correlates with their therapeutic resistance.
the cscs can hijack normla stem cell niches. these niches have various factors and cells to maintain the stemness of cscs and support their survival. in the niche, cscs can upregulate epithelial-mesenchymal transormation pathways (emt) in the surrounding nontumorigenic cells and transform them into cscs to further support the cscs to colonise the new niche.
primary cscs can also manipulate distant tissue niches to create a metastatic niche for their future arrival. the primary tumour sends off growth factors which induce chemotactic protein expression and ecm remodelling in the metastatic sites which creates the pre-metastatic niche,
cscs initiate their metastatic outgrowth around blood capillaris created by perivascular niches enriched in angiocrine factors. as the niche is established, cscs recruit stromal cells to establish the paracrine loops to supply cscs with growth factors for their maintenance. at the meantime, the surrounding stromal cells secrete proteases to further remodel the ecm to allow tumour expansion.
Stem cell niche as a therapeutic target?
buiphysical parameters that comprise the local microniche surrounding a single cell?
soluble factors
- growth factors
- differentiation factors
- hormones
- ph
nature of matrix
- fibronectin
- collagen
- laminin
matrix mechanics
- rheological properties
- crosslinking density
matrix topography
- nanostructure
- fibrillar structure
confinement
- restricted spreading
- columnar shape
- compressive forces
geometry
- 1D, 2D, 3D
- cell shape
spatial distribution of adhesive cues
juxtacrine interactions
-cell-cell junction interactions
0juxtacrine signalling
- gap junction
external mechanical stimuli
- shearflow
external tension
-acto-myosin contraction
-compression
in vitro culturing: epidermal stem cell niche?
Traditional approaches to investigate cell-ECM interactions are represented by two-dimensional (2D) keratinocyte culture on surfaces coated with adhesive proteins or a mix of proteins. Certain ECM molecules have been found to play essential role in maintaining cells in undifferentiated state. Stem cells express high levels of α2β1, α3β1, α5β1-integrins, and adhere rapidly to type IV collagen, fibronectin, and the ECM that is deposited by cultured keratinocytes [68]. In culture, β1-integrin activation suppresses the terminal differentiation of keratinocytes [116]. Laminin-511 can support embryonic stem cell self-renewal in the absence of differentiation inhibitors and at low cell density [117,118]. Engineered 2D micropatterned substrates as well as hydrogels helped to elucidate the behaviour of epidermal cells [119,120]. It was shown that the matrix area [119] and its stiffness [120], rather than ECM concentration or composition are essential for keratinocyte differentiation, suggesting that biophysical factors may be more important in determining the stem cell fate. To this end, it may be of interest that changes in ECM mechanics and in cell shape are transmitted to the cell nucleus and regulate gene transcription programs [121].
