Introduction

Tissue structure homeostasis, function, and renewal depend on cellular composition. Generally, terminally differentiated cells define the structure and normal function of tissue and organs, while the adult stem and progenitor cells determine renewal and regeneration potential [1,2,3]. Stem cell stability is based on the sustainable work of cell signaling pathways, which is controlled by intracellular (non-coding RNAs and transcription factors) and extracellular (growth factors, morphogens, environmental cues) factors [4, 5]. Changes to microenvironment conditions cause the transition of stem cells from a quiescent to an activated state, which initiates proliferation and differentiation [6, 7]. The combination of external microenvironmental factors that support the functioning of stem cells has been labelled a “stem cell niche” [8]. An integral component of the niche is the extracellular matrix (ECM), which provides most of the clues from the microenvironment, i.e., physical characteristics, the conduction of specific signals from structural components, and the anchorage of components to the ECM, e.g., soluble factors (growth factors and morphogens) and matrix-bound vesicles [9]. Thus, the ECM stimulates various intracellular signaling cascades required to maintain the homeostasis of stem cell niches [10]. Herefore, interpreting the research results obtained from cells isolated from their microenvironmental context is complex.

Stem cell niches contain cells that regulate the maintenance of stem cells homeostasis and fate through the secretion of various niche components. Almost in all tissues and organs mesenchymal stem/stromal cells (MSC) play this role being the critical regulators of stem cell niche functioning [11,12,13,14,15]. MSC can secrete a variety of niche ECM components, paracrine factors, and bioactive molecules within extracellular vesicles in response to changes in the microenvironment (e.g., injury). In addition, under activating stimuli, multipotent stem cell subpopulation of MSC is capable of self-renewal of their own pool as well as differentiation, leading to modification of the microenvironment by replenishing deficient components or recruiting other supporting cells to the niche [16, 17]. According to one of the minimal criteria to define multipotent MSC are capable of adipogenic, chondrogenic and osteogenic differentiation in vitro [17]. Until recently, scientists used the term "mesenchymal stem cells" to discuss these cells, but it was considered incorrect due to the collected data proving that the main physiological function of MSC is not exclusively the presence of stem cells [18]. Therefore, the current recommended name is “mesenchymal stromal cells”, and the presence of multipotent stem cells in MSCs should be carefully evaluated using appropriate tests [17]. Nonetheless, all MSC are heavily reliant on the ECM clues, so we focus on these cells to analyze the diversity of ECM-induced signal pathways in postnatal stem cells.

The interaction of cells with the microenvironment, in particular with the components of the ECM, is mediated by specific receptors, leading to the activation of various signaling cascades within the cell and, as a consequence, to changes in its behavior. Looking at the identification of the main receptors and participants in ECM signaling cascades from a historical point of view can help to summarize the knowledge on this issue in the field of matrix biology (Table 1). Even though many receptors and key participants of their signaling cascades have been known for a long time, there are many gaps among the other participants of these cascades, as well as in the case of changing microenvironment and the nature of their network interactions, and for a specific type of cell. This tendency highlights the importance of the analytical reviews covering the mechanisms of ECM-mediated regulation of cell function, here in particular the stem cell differentiation. In parallel with investigation of the ECM, the signaling cascades of postnatal stem cells remain an important issue for cell and matrix biology and regenerative medicine. In this review, we focus on analyzing the data obtained from MSC in vitro and in vivo for a better understanding of the regeneration processes relevant to native postnatal stem cells. Accumulating ECM signaling observations, we suggest a system biology-based approach for examining the predicted networks of such signal transduction pathways on the example of DDR1-initiated signaling in MSC.

Table 1 General discovery dates for ECM signaling molecules
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ECM receptor signaling pathways during MSC differentiation

Many ECM components were found in stem-cell niches, including collagens, laminins, fibronectin, and proteoglycans [43], and also paracrine factors affecting the interaction of stem cells with the ECM [44]. The ECM supports the appropriate position of cells within their microenvironment and regulates such properties as proliferation, polarization, migration, and differentiation [45]. Several studies have demonstrated that the ECM directs the differentiation of stem cells into specialized cells of the organ from which it was isolated. This data confirms that the ECM has tissue specificity for maintaining a certain niche [46].

It is presumed that the tissue specificity of the ECM is provided due to differences in the cellular composition of tissue types. Nevertheless, it is known that cells with similar phenotypes and functions isolated from different tissue types differ in the expression profile of ECM proteins. Thus, a comparative proteomic analysis of the ECM, secreted by MSC from bone marrow or adipose tissue, showed the presence of unique sets of proteins produced by each cell type. This allows us to assume that ECM tissue specificity is established at histo- and organogenesis stages and subsequently maintained throughout life [47]. The composition of ECM components, which are distinguished not only among different tissues and organs but also within niches, was confirmed for niches of the intestinal crypt, hematopoietic niche, and limb [48, 49]. Such diversity among ECM components within the niche provides a further indication for stem cell outcomes. Each component supports important functions, from kee** the stem cell in the quiescent state to asymmetric division, migration along to ECM components or soluble factors, and the termination of differentiation [50,51,52]. These functions are mediated by the activation of a specific signal cascade. The interaction of participants in the cell signaling pathways, including MSC, with the microenvironment is carried out using special molecules, the most important of them are discussed below.

Integrins

The main class of ECM receptors is integrins, heterodimeric proteins comprising α and β subunits. There are 18 determined α-subunits and 8 β-subunits in humans, and these are responsible for recognizing ECM proteins and their physical properties (e.g., stiffness and stretching), and for intercellular communications. Some reviews can provide more detailed information on modern representations of the structure of integrins [53,54,55].

Integrins realize bi-directional signaling. The high-affinity interaction between integrins and their ECM ligands activates the “outside-in” signaling pathway. Then, focal adhesion kinase (FAK) and Src-mediated phosphorylation of the integrin adhesion complex (IAC) and cytoskeletal components initiate intracellular molecular reorganization and phosphorylation events among many adapters [56]. Crosstalk between FAK and Src kinases provides signaling pathways induced by mechanical forces and RTK signaling, leading to control of stem cell fate transitions [57]. For example, initiation of FAK/Src/Rac1-mediated myosin IIA recruitment into FAs increased the osteogenic commitment of human bone marrow MSC [58]. On other occasions, intracellular signals interact with the cytoplasmic tails of integrins, which leads to conformational changes in the extracellular ligand binding domain. This mechanism fine-tunes the control of ligand affinity [56, 59].

Integrins are considered crucial receptors for stem cell functioning. Various integrins are widely represented on the surface of different types of stem cells [60]. Subunit β1 is often associated with stem cell phenotype because, for several tissue-specific stem cells, this integrin supports the homing to stem-cell niche [61, 62], the maintenance of stemness [63], and the quantity of stem/progenitor cells in tissue [64].

There is no exception in the case of MSC. It has been shown that integrins α2β1 or α11β1 provide adequate interaction of human bone marrow MSC with type I collagen, which ensures cell survival and osteogenic differentiation by activating the protein kinase B (PKB/Akt) survival pathway [65]. Similar results were obtained in the study of integrin α5 activated signaling cascades in human bone marrow MSC during osteoblast differentiation. In this case, osteogenic differentiation of human bone marrow MSC was mediated by activation of FAK/ERK1/2 MAPKs and PI3K signaling pathways [66, 67]. Knockdown of α2 integrin in human bone marrow MSC during osteogenic differentiation on stiffer matrices was downregulated by ROCK, FAK and ERK1/2 axis [68]. Involvement of integrin α2 in human bone marrow MSC osteogenesis through activation of the p38 MAPK pathway was also demonstrated [69]. Results of another study showed that integrins in rat bone marrow MSC activate FAK-GSK3β phosphorylation, which prevents β-catenin degradation and nuclear translocation to bind to the wnt1 promoter [70]. In addition, silencing of the β1 subunit reduces both osteogenic and chondrogenic differentiation of human bone marrow MSC [71].

Discoidin domain receptors

Discoidin domain receptors (DDRs) (DDR1 and DDR2) are collagen-binding receptors in mammals [72]. Several articles have described the structure and existing isoforms of DDRs [73,74,75,88,89,90]. The activation of certain signaling pathways through CD44 is conditioned from the molecular weight of HA. CD44 is responsible for the migration/homing and differentiation of stem cells [85, 91,92,93]. The Wnt-induced/β-catenin signaling pathway is crucial for MSC commitment in osteogenic differentiation [94], and CD44 has a complex role because it is one of the gene targets and regulators of Wnt activation [85]. Moreover, CD44 is a key regulator of chondrogenic differentiation of human adipose-derived stem cells and human amniotic MSC via ERK1/2 signaling [95,96,201].

In this review, we discussed the results of recent studies covering the participation of cellular receptors to ECM components in the maintenance of postnatal tissue homeostasis as well as tissue regeneration after various types of damage through the regulation of MSC functions. We also focused on summarizing the data of the currently known ECM-induced signaling cascades in human stem and progenitor cells. However, literature analysis revealed that very few and only the most common participants of these signal pathways are investigating; moreover, they are involved in multiple cellular processes which makes them not suitable as a potential therapeutic target to modulate stem cell functioning for the purposes of regenerative medicine. Therefore, to detect more specific ECM-induced signaling pathways in stem and progenitor cells as well as to search for novel targets for fine-tuning regeneration processes, we suggest using the approaches of systems biology.

Utilizing the established changes in the stem cell profile of ECM receptors (Step 1), it is possible to build predictive networks of PPIs (Step 2). Such networks can be analyzed based on the well-known and available databases described in this review. After receiving the list of participants in the signaling cascade, a normalization step can be added to the data of the proteome or transcriptome of cells of interest to researchers (Step 3). Then, the created network can be compared with a database of known signal pathways to select specific signaling pathways and processes accumulating the most of participants from the previously predicted network of PPIs (Step 4 and Step 5). The resulting theoretical model could be useful in designing the further experimental research exploring the ECM-mediated regulation of stem and progenitor cells (Fig. 5).

Fig. 5
figure 5

Summary illustration of review

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This review is the first to detail the major types of ECM receptors in postnatal stem cells, using MSC as an example, and to evaluate the involvement of ECM-induced signaling cascades in the process of MSC differentiation. In addition, a detailed algorithm of action using state-of-the-art methods in the field of systems biology is proposed to explore the variability of ECM signaling pathways in different cells. It may help other researchers in the field to discover new targets for tissue and organ regeneration with the ability to fine-tune cellular mechanisms rather than inhibiting members of cascades that are responsible for multiple processes and could potentially lead to pathology or cell death (e.g., such as Src, Erk, Akt).

Shortly, we suppose that the suggested approach of generating the predictive networks of PPI could serve as a useful tool which is complementary or even partially replacing the omics experimental work. Combining the known data about ECM receptor on the specific target cells and desirable functional processes one could reveal novel expected or unexpected signal transduction pathways induced by ECM. Few examples are demonstrated in the review. Indeed, these results have limited value until experimental validation. However, the suggested algorithm could intensify the search of ECM-induced signaling pathways in stem and progenitor cells and shorten the time to the potential breakthroughs in the field.

Thus, following the current trends in the field of matrix biology, it could allow to identify new promising directions in the study of stem and committed cell behavior within their matrix microenvironment. Importantly, these approaches expand the number of tools in regenerative medicine using to search for the mechanisms regulating tissue and organ renewal and repair.