Human mesenchymal stem cells (MSCs) hold great promise for tissue regeneration. During tissue repair, MSCs migrate to the sites of injury and participate in the repair process [1, 2]. Stem cell migration not only plays a potential role in cell colonization inside biomaterial scaffolding , but also takes part in the reorganization of matrix . Moreover, the guided migration of MSCs creates a therapeutic environment for bone regeneration . These features emphasize the importance of targeted stem cell migration in tissue-engineering approaches.
Stem cell migration improves the curative ability of diseased tissues via appropriate homing inside injured sites [1, 2, 6]. Previously, it was reported that cell migration and subsequent suitable colonization of progenitor stem cells within injured sites accelerate myocardial regeneration [7, 8], reduce heart damage [9, 10], aid in recovery from spinal-cord injuries , cure nerve damage , and repair cartilage [13, 14]. The MSCs have the potential to migrate through bone marrow endothelium, by using the regulatory mediators of matrix metalloproteinase-2 and tissue-inhibitor metalloproteinase-3 . The administration of allogenic MSCs, whether derived from bone marrow or from adipose tissue, was reported for cellular proliferation, neurogenesis, and takes part in the functional recovery of brain after ischemic stroke . Moreover, clinical trials of using human MSCs for bone fractures, bone defects, and cartilage disorders have been performed [17–19]. The investigation of targeted stem cell migration could be beneficial for tissue regeneration, especially for cartilage restoration. Chondrocytes in the articular cartilage lack innervations and vascularization and have low mitotic potential. Moreover, the chondrocytes have no physical contact to each other and entrapped into extracellular matrix [20–22]. These features make cartilage restoration is a hot issue in case of regeneration.
Autologous chondrocyte transplantation is an established technique for cartilage repair [23–25], which consists of chondrocyte isolation, in vitro dedifferentiation, and transplantation [25–27]. It is established that dedifferentiation is necessary to achieve a high cell number, and it is considered a curative step in such technologies [28–30]. However, massive dedifferentiation of chondrocytes results in loss of the chondrogenic phenotype and formation of primitive multipotent cell types [28–31]. To overcome such shortcomings, chondrogenic maintenance cues such as cytokines, chemokines, and growth factors are required to regulate and control the process of chondrocyte transplantation. The theoretic assumption is that this would increase remedial time and therapeutic cost because of in vivo posttransplantational procedures for chondrogenic differentiation and maintenance. It necessitates the use of such culture techniques and cell types, which not only maintain a chondrogenic-specific phenotype, from the beginning of transplantation, but also proliferate to increase the number of cells.
Therefore, the direct mobilization of endogenous cells and subsequent migration to the point of injury could be a promising approach for cartilage regeneration. In this context, the motility and migratory features of chondrocytes have been characterized . To investigate the migratory effect of serum- or CCL25-mediated chemotaxis on chondrogenic cells, we isolated differentiated cells from compact pellets, after 28 days of chondrogenic differentiation. They maintained the chondrogenic nature for about 14 days in the culture and were able to proliferate. After chondrogenic confirmation, their surface profile and cell-migration ability were examined for serum- or CCL25-mediated chemotaxis.
Present strategies of stem cells transplantation advocate the use of MSCs [23, 33–35], for diverse regenerative application, including cartilage repair [23, 26]. In some cases, the clinical use of MSCs is considered more valuable than autologous chondrocytes transplantation [36, 37], as it requires one less knee surgery, is easy to isolate, has a high proliferative rate, reduces cost, and provides better regenerative efficiency [28, 35, 36]. For instance, the use of magnetized MSCs is the best choice for articular cartilage repair . In such cases, one controversial and basic question needs an answer: which cell type would be more suitable for cartilage regeneration, undifferentiated MSCs or their chondrogenic differentiated progeny? Therefore, we investigated the cell-migration profile of chondrogenically differentiated cells compared with the undifferentiated and dedifferentiated states of MSCs, according to already described formulation and concentration of allogenic serum .
However, allogenic serum has a complex composition [40–42], which is unknown and undefined for some molecular functions. It emphasizes the need for a defined and targeted chemokine, to make the present regenerative strategies more valuable and beneficial for appropriate cell homing. Moreover, chemokines are recognized as an essential factors for diverse cellular process including activation of the central hub of cellular migration via direct or indirect mechanisms and signaling events [39, 43–45], and stimulation of the therapeutic efficiency of regeneration.
Chemotaxis is defined as directional movement of cells toward concentration gradients or chemoattractants, whereas chemokinesis is random cell movement without any chemoattractants . Directional migration of MSCs to the site of injury is controlled by several factors, such as hypoxia and the Rho family of GTPases [47, 48]. Generally, tissue regeneration requires a coordinating and well-regulating cell migration for its restoration in response to different cues like cytokines and growth factors [43, 49]. Apart from this, chemokines play a vital role in a biologic plethora of migration and are considered guided cues for directional and targeted stem cell trafficking [39, 43, 49]. Chemokines enable the activity of migratory processes in hematopoietic and nonhematopoietic cells , navigate the cellular trafficking between tissue compartments, and play a potential role in cell activation, differentiation, survival, and recruitment of leukocytes . In addition, they play a decisive role in mobilization of T lymphocytes during allergenic reactions  and contribute to the complex pathophysiology of asthma by using the coordinating network of cellular activation and signaling web .
Chemokine-based recruitment of MSCs to the point of injury is a promising approach, whereas chemokine (C-C motif) ligand 25 (CCL25) could play a vital role in cell migration [44, 54]. After nerve damage or myocardial infarction, the mutual interactions of chemokines and their receptors mediate the migration of MSCs to injured sites . Obviously, to understand the underlying mechanism would be of interest. In this context, CCL25 has been suggested as a potential chemoattractant for the directional movement of MSCs , and C-C chemokine receptor type 9 (CCR9) is known as a cognate receptor of CCL25 [57, 58]. To check whether the chondrogenic differentiated state of MSCs affects the cell-migration rate, we performed the chemotaxis assay for undifferentiated, chondrogenic differentiated and dedifferentiated cells, by using the chemokine CCL25 . Furthermore, the receptor CCR9 was examined in different states of MSCs, as CCR9 is an established known receptor of CCL25 and plays a decisive role in the targeted migration of stem cells [43, 44, 54].
To cope with the challenges of the growing tissue-engineering industry, we need an appropriate cell source and suitable cell types, which are able not only to migrate to the site of injuries or damage in a well-guided way, but also to facilitate quick regeneration. Our introduced cell types could be valuable and beneficial in this regard.