Abstract
Much of the current research in regenerative medicine concentrates on stem-cell therapy that exploits the regenerative capacities of stem cells when injected into different types of human tissues. Although new therapeutic paths have been opened up by induced pluripotent cells and human mesenchymal cells, the rate of success is still low and mainly due to the difficulties of managing cell proliferation and differentiation, giving rise to non-controlled stem cell differentiation that ultimately leads to cancer. Despite being still far from becoming a reality, these studies highlight the role of physical and biological constraints (e.g., cues and morphogenetic fields) placed by tissue microenvironment on stem cell fate. This asks for a clarification of the coupling of stem cells and microenvironmental factors in regenerative medicine. We argue that extracellular matrix and stem cells have a causal reciprocal and asymmetric relationship in that the 3D organization and composition of the extracellular matrix establish a spatial, temporal, and mechanical control over the fate of stem cells, which enable them to interact and control (as well as be controlled by) the cellular components and soluble factors of microenvironment. Such an account clarifies the notions of stemness and stem cell regeneration consistently with that of microenvironment.
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Change history
09 December 2022
A Correction to this paper has been published: https://doi.org/10.1007/s10441-022-09455-1
Notes
In the current literature, the causal role of microenvironment is sometimes referred as ‘promotive’ or ‘protective’, inasmuch as it can promote the activation or inhibition of cellular mechanisms that protect against tissue degradation.
Throughout the paper, by ‘tissue microenvironment’, we mean a system of relations among the extracellular matrix, cellular, and non-cellular elements. Accordingly, we will mainly focus on the organization of the extracellular matrix in solid tissues and how it interacts with cellular and non-cellular elements.
Another key target of stem-cell therapy is the bone marrow tissue for the treatment of leukaemia and multiple myeloma. As further pointed out in Sect. 5, the bone marrow extracellular matrix exerts a less rigid control on hematopoietic stem cells, thus not clearly elucidating the relationship between tissue microenvironment and stem cells. For this reason, we think that an in-depth analysis of solid tissues, such as those of the cardiac and nervous system, is more explanatorily relevant than that of the semisolid tissue of bone marrow.
An example is provided by scaffolds consisting of collagen and polyglycolic acid and seeded with patient’s urothelial and smooth muscle cells (Sampogna et al. 2015).
In the asymmetric division, a stem cell generates one differentiated cell and one stem cell. In the symmetric division, a stem cell gives rise to two differentiated cells or two stem cells (Shahriyari and Komarova 2013).
Self-renewal and proliferation, in spite of being closely linked to cell division, are not the same: the former refers to a regulated process of cellular division leading to daughter cells with reproductive capacities; the latter designates the production of daughter cells that are not necessarily tightly regulated (as in the case of tumor proliferation) and not necessarily able to reproduce (He et al. 2009).
Other adult tissues (extracted, for example, from liver, skeletal muscle, kidney, and urothelium) can be potential sources of adult stem cells, as their progenitors can proliferate and differentiate into specific organ cell types (Yalcinkaya et al. 2014).
An interesting example of adult stem cells is provided by mesenchymal stem cells, which may differentiate in vitro in a variety of cell types such as hematopoietic stem cells, adipocytes, osteocytes, and chondrocytes (Uccelli et al. 2008).
The reprogramming of human somatic cells into induced pluripotent stem cells is obtained by inducing abnormal gene expression of a core of transcription factors (OCT4, SOX2, and NANOG) that governs pluripotency (De Los Angeles et al. 2015).
Stem cell niches have been characterized in many different tissues such as the bone marrow, skeletal muscle, central and peripheral nervous system (see Votteler et al. 2010).
Cardiomyocytes are tubular muscle cells that contains myofibrils (protein fibres sliding past each other) organized into sarcomeres (the fundamental contractile units of muscle cells). The membrane and the interior of cardiomyocytes are connected through protrusions of cardiomyocytes membrane (T-tubules).
Fibroblasts are cells that synthesize the components of the extracellular matrix (e.g., collagen) and produce the structural framework (the stroma) for animal tissues.
In physics, stiffness is the strain of an elastic body expressed as a function of the force producing the strain. The stiffness of healthy tissue microenvironments requires a balance between rigid-like (elastic) and dissipative (viscous) components (Cameron et al. 2011).
Hypoxia-inducible factors are transcription factors promoting vascularization.
Transdifferentiation is an artificial process in which one mature somatic cell is transformed into another mature somatic cell without undergoing an intermediate pluripotent state or progenitor cell type.
Paracrine signals include all those molecules travelling over a relatively short distance (local action) and modifying nearby cells.
The different types of stem cells produce different degrees of neovascularization in infarcted hearts (Müller et al. 2018).
Although it is known that stem cells modulate the extracellular matrix of cardiomyocytes, the exact mechanisms underlying it is not fully known.
The production of immune cells is promoted by free radicals, which favor chemotactic migration of inflammatory cells into the injured tissue microenvironment, and by the infiltration of leukocytes into the infarcted tissue in response to the chemokines’ expression (Khodayari et al. 2019).
IL-1R stands for interleukin 1 receptor; APO1 for the apoptosis antigen 1; TRAIL-R for the TNF-related apoptosis-inducing receptor.
A more detailed characterization of the process of mechanotransduction and how it affects stem cell fate is done in Sect. 5.
Since it is very difficult to experimentally manipulate the ECM stiffness in vivo, the effects of the stiffness/flexibility of the ECM on stem cells are usually studied on artificial matrixes that mimic tissue elasticity (Gattazzo et al. 2014).
‘Durotaxis’ is the name given to the process of cell migration driven by stiffness differences in the substrate.
In some cases, although some murine induced pluripotent stem cells and embryonic stem cells have been shown to differentiate to cardiomyocytes at 2% or 5% of oxygen tension, either they do not survive or generate ineffective beating cardiomyocytes (Brodarac et al. 2015).
Peripheral nervous system consists of nerves that can regenerate after injury because of the supportive growth environment of Schwann cells (Bhangra et al. 2016). Stem cell therapy can also be employed for repairing peripheral nerve injuries in order to regenerate a lost tissue (Goncalves and Przyborski 2018).
After injury, the tissues of the central nervous system produce glial scar that hinders neuroregeneration. Glial scar formation is a reactive process during which astrocytes abnormally increase after injury to the central nervous system.
Compared to most drugs for the treatment of neurodegenerative diseases, which cannot target neuronal cell death and are not able to arrest neurodegenerative processes, stem cells can promote neural regeneration (e.g., endogenous neuronal growth, synaptic connection, neural proliferation, angiogenesis) and prevent neural cells from further degeneration (e.g., anti-apoptosis, anti-fibrosis, and anti-inflammatory effects) (Das et al. 2019).
Most of current studies on stem cell therapy for the treatment of neurodegenerative diseases are preclinical and it has not yet evaluated the tolerance and efficacy in clinical trials (Sivandzade and Cucullo 2021).
Aβ peptides activate GSK-3β signalling pathways, which decrease β-catenin levels and impair neurogenesis of human neural stem cells (Lee et al. 2013).
Brain ECM consists of three main parts -the basement membrane, the perineuronal net, and the neural interstitial matrix- and includes cells that are placed in proximity with a limited stromal space. Compared to the ECM of other tissues, the brain one lacks some components that are commonly found in other organs (e.g., fibronectin and collagen) and exhibits different types of proteoglycans that are localized to intercellular spaces between neurons and glia (Bonneh-Barkay and Wiley 2009).
Both in Alzheimer’s and Parkinson’s diseases, there is a change in the stiffness or elasticity of the ECM: in Alzheimer’s it is a change in ECM, whereas in Parkinson’s a change in the stiffness/elasticity of substantia nigra (Barnes et al. 2017). In multiple sclerosis, the central nervous system basement membrane become discontinuous and levels of fibrillar collagen increase, leading to perivascular fibrosis (Barnes et al. 2017).
The stiffness of brain ECM affects the mechanical signals that are sent to focal adhesion protein complexes, which regulate neural differentiation through the phosphorylation of focal adhesion kinase (FAD) and also cytoskeleton rearrangement through the Rho/ROCK, Src family kinases, and ERK1/2 signaling pathways (Mammoto et al. 2012).
Softer substrates are less than 1000 Pa, whereas stiffer substrates are between 1000 and 10,000 Pa.
Brain injury determines not only a mechanical breakdown of brain tissue and necrotic death, but also a cascade of cellular events (e.g., oxidative stress, mitochondrial dysfunction, and blood-brain barrier disruption) that contribute to a pro-inflammatory microenvironment that ultimately leads to the infiltration of immune cells (microglia) into the damaged brain parenchyma (Bonilla and Zurita 2021).
Ischemic brain is characterized by high rates of apoptosis and necroptosis, the release of damaged-associated molecular patterns and matrix metalloproteinases, leading to inflammatory responses such as astrocyte and microglia activation, the release of cytokines and chemokines, and infiltration of leukocytes and neutrophils (Liu et al. 2021).
Neurodegenerative diseases are characterized by the secretion of proinflammatory cytokines (e.g., tumor necrosis factor-α, interleukin-1β, and interleukin-6) that trigger neuroinflammation (Russo et al. 2011).
In more philosophical terms, we could say that biological practice tends to provide mereological accounts of microenvironment by focusing on how the (local) mechanisms performed by microenvironment components affect cellular behaviour.
This consideration applies in general to the relationship between cells and tissues.
Here, by ‘physiological integration’, we mean that the cellular behavior of stem cells (e.g., metabolism, life cycle, motility, communication) depends on the overall physiological behavior and homeostasis of their microenvironment.
ECM stiffness is linearly related to ECM stress, so that “the cellular control of ECM stress is equivalent to controlling ECM stiffness” (Humphrey et al. 2014, p. 805).
The alteration of cell-cell and cell-ECM adhesion molecules may promote cell migration and uncontrolled cell growth. In physiological conditions, when non-hematopoietic cells detach from ECM, they undergo a specific kind of apoptotic death (anoikis) that prevent them from migrating and invading other tissues. However, this mechanism fails in cancer, thus favoring invasion processes (Paoli et al. 2013).
The loss of apical-basal polarity can favor basal extrusion and alterations in cell extrusion, which ultimately lead to tumorigenesis (Chatterjee et al. 2016).
More generally, the motility of cells is collectively controlled during morphogenesis and carcinogenesis.
The transmission of force from a cell to another is based on the coupling of cell-cell junctions and actomyosin.
From an epistemic point of view, the concepts of ‘dispositional property’ and ‘relational and systemic property’ are incompatible, because the former refers to an intrinsic property of stem cells, whereas the latter to an extrinsic one (Laplane 2015, 2016). However, from an ontological point of view, a dispositional property can be compatible with a relational and systemic property, since the functions of biological entities “are defined primarily by the context they are embedded within, and hence by the web of relations they are part of” (Bertolaso and Ratti 2018, p.1).
As also stressed by an anonymous reviewer, our reciprocal and asymmetrical account of the stem cells-microenvironment relationship could eventually suggest that relational and dispositional views are opposite sides of the same coin: in both cases, the stemness is a context-dependent property; however, the difference lies in that in the first case only a small and defined category of cells can behave as stem cells, whereas in the latter which cell will act as a stem cell is much more flexible.
We warmly thank an anonymous referee for having pointed out this aspect.
Bertolaso (2016) describes this difference in causal explanation by distinguishing between a ‘by holding’ and a ‘by doing’ causation.
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Militello, G., Bertolaso, M. Stem Cells and the Microenvironment: Reciprocity with Asymmetry in Regenerative Medicine. Acta Biotheor 70, 24 (2022). https://doi.org/10.1007/s10441-022-09448-0
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DOI: https://doi.org/10.1007/s10441-022-09448-0