Analysis of chemotactic molecules in bone marrow-derived mesenchymal stem cells and the skin: Ccl27-Ccr10 axis as a basis for targeting to cutaneous tissues

Abstract

Background aims The adult stem cells produce a plethora of extracellular matrix (ECM) molecules and have a high potential as cell-based therapeutics for connective tissue disorders of the skin. However, the primary challenge of the stem cell-based approach is associated with the inefficient homing of systemically infused stem cells to the skin. Methods We examined chemotactic mechanisms that govern directional migration of the mesenchymal stem cells (MSCs) into the skin by conducting a comprehensive expression analysis of chemotactic molecules in MSCs and defined cutaneous tissues from normal and hereditary epidermolysis bullosa (EB)-affected skin. Results Analysis of chemokine receptors in short and long-term MSC cultures showed tissue culture-dependent expression of several receptors. Assessment of epidermis- and dermis-derived chemokines showed that majority of skin-originated chemotactic signals preferentially recruit different sets of leukocytes rather than MSCs. Analysis of the chemotactic molecules derived from EB-affected non-blistered skin showed only minor changes in expression of selected chemokines and receptors. Nevertheless, the data allowed us to define Ccl27-Ccr10 chemotactic axis as the most potent for the recruitment of MSCs to the skin. Our in vivo analysis demonstrated that uniform expression of Ccr10 on MSCs and alteration of Ccl27 level in the skin enhance extravasation of stem cells from circulation and facilitate their migration within cutaneous tissue. Conclusions Collectively, our study provides a comprehensive analysis of chemotactic signal in normal and EB-affected skin and proof-of-concept data demonstrating that alteration of the chemotactic pathways can enhance skin homing of the therapeutic stem cells.

Pro-Inflammatory Chemokines and Cytokines Dominate the Blister Fluid Molecular Signature in Patients with Epidermolysis Bullosa and Affect Leukocyte and Stem Cell Migration

“…Increased levels of CCL2, CCL19 and CCL20 were observed in the skin of EBS mice (Annicchiarico et al, 2015, Heinemann et al, 2011, Lettner et al, 2013, Roth et al, 2009). Our prior studies also identified reduced transcription of CCl27, CSF3, CX3CL1 and CXCL14 and higher expression of CXCL18 in the non-blistering skin of JEB and DEB transgenic mice (Alexeev et al, 2013). Proteomic screens of chemotactic molecules in BF of DEB blistering mouse skin showed consistently high levels of CCL6, chemerin, CCL8, CCL9/CCL10, CCL12, CXCL1, CXCL2, CXCLl2, CXCL5, and CDF (Alexeev et al, 2016).…”

“…As discussed previously (Alexeev et al, 2013, 2016), migration of cells to peripheral tissues is a two-step process requiring (i) extravasation of cells from the blood stream, and (ii) migration of cells within the peripheral tissue (skin). Usually, separate sets of chemokines regulate these two processes.…”

“…Usually, separate sets of chemokines regulate these two processes. Extravasation of memory T cells from dermal blood vessels is mediated by CCR4 ligands (CCL17, CCL22 and CCL5) (Tubo et al, 2011), whereas migration of cells within the tissue requires activation of other receptors (e.g., CCR10) by epithelia-derived CCL27 (Alexeev et al, 2013). Separation of extravasation and in-tissue migration chemotactic signals helps restrict migration of circulating cells to the injured sites.…”

Scintigraphic Tracking of Mesenchymal Stem Cells After Intravenous Regional Limb Perfusion and Subcutaneous Administration in the Standing Horse

“…MSC administration to the subcutaneous space might lead to better local persistence. Also, given appropriate chemotactic signals, homing of MSC within cutaneous tissues has been reported . Therefore, peritendinous MSC injections are conceivably a treatment modality for tendon injuries through paracrine effect or secondary migration to the tendon.…”

Placenta-based therapies for the treatment of epidermolysis bullosa

“…Immunofluorescence analysis of the skin of pups that survived three weeks post-transplant revealed patchily distributed C7, estimated to be about 15% that of wild type C7 levels. Remarkably, when the skin of these transplanted pups was subjected to a mechanical stress test, separation along the DEJ did not occur suggesting that even a partial restoration of C7 could provide clinically meaningful benefits [33]. Around the same time, Congent et al injected BM MSCs from an unrelated donor intradermally near the wounds of two patients with RDEB.…”