Mesenchymal Stromal Cell Secretome for Therapeutic Application in Skin Wound Healing: A Systematic Review of Preclinical Studies.

Non-healing skin wounds remain a challenge in the healthcare system. In this sense, it is suggested that the secretome of mesenchymal stromal cells (MSCs) can be effective as a therapeutic strategy for regenerative medicine. Therefore, this systematic review aimed to determine the effects of treatment with a secretome derived from MSCs on the healing of skin wounds in a preclinical model of rodents (mice and rats). Studies were systematically retrieved from 6 databases and gray literature that provided 1,172 records, of which 25 met the inclusion criteria for qualitative analysis. Results revealed substantial heterogeneity among studies concerning experimental designs and methodologies, resulting in a high risk of bias. Together, the selected studies reported that treatment improved wound healing by (1) accelerating wound closure and improving skin repair quality; (2) reducing inflammation by decreasing the number of cells and inflammatory cytokines, accompanied by polarization of the M2 macrophage; (3) complete re-epithelialization and epidermal reorganization; (4) neovascularization promoted by proliferation of endothelial cells (CD34+) and increased levels of pro-angiogenic mediators; (5) better scar quality promoted by increased expression of collagen types I and III, as well as improved deposition and remodeling of collagen fibers. In conclusion, despite the need for alignment of methodological protocols and transparent reports in future studies, results show that the secretome of MSCs from different tissue sources corresponds to a promising tool of regenerative medicine for the treatment of skin wounds.

Human adipose-derived mesenchymal stromal cells from face and abdomen undergo replicative senescence and loss of genetic integrity after long-term culture.

Body fat depots are heterogeneous concerning their embryonic origin, structure, exposure to environmental stressors, and availability. Thus, investigating adipose-derived mesenchymal stromal cells (ASCs) from different sources is essential to standardization for future therapies. In vitro amplification is also critical because it may predispose cell senescence and mutations, reducing regenerative properties and safety. Here, we evaluated long-term culture of human facial ASCs (fASCs) and abdominal ASCs (aASCs) and showed that both met the criteria for MSCs characterization but presented differences in their immunophenotypic profile, and differentiation and clonogenic potentials. The abdominal tissue yielded more ASCs, and these had higher proliferative potential, but facial cells displayed fewer mitotic errors at higher passages. However, both cell types reduced clonal efficiency over time and entered replicative senescence around P12, as evaluated by progressive morphological alterations, reduced proliferative capacity, and SA-ß-galactosidase expression. Loss of genetic integrity was detected by a higher proportion of cells showing nuclear alterations and γ-H2AX expression. Our findings indicate that the source of ASCs can substantially influence their phenotype and therefore should be carefully considered in future cell therapies, avoiding, however, long-term culture to ensure genetic stability.

Mesenchymal stromal cells from dermal and adipose tissues induce macrophage polarization to a pro-repair phenotype and improve skin wound healing.

The process of wound healing restores skin homeostasis but not full functionality; thus, novel therapeutic strategies are needed to accelerate wound closure and improve the quality of healing. In this context, tissue engineering and cellular therapies are promising approaches. Although sharing essential characteristics, mesenchymal stromal cells (MSCs) isolated from different tissues might have distinct properties. Therefore, the aim of this study was to comparatively investigate, by a mouse model in vivo assay, the potential use of dermal-derived MSCs (DSCs) and adipose tissue-derived MSCs (ASCs) in improving skin wound healing. Human DSCs and ASCs were delivered to full-thickness mouse wounds by a collagen-based scaffold (Integra Matrix). We found that the association of both DSCs and ASCs with the Integra accelerated wound closure in mice compared with the biomaterial only (control). Both types of MSCs stimulated angiogenesis and extracellular matrix remodeling, leading to better quality scars. However, the DSCs showed smaller scar size,superior extracellular matrix deposition, and greater number of cutaneous appendages. Besides, DSCs and ASCs reduced inflammation by induction of macrophage polarization from a pro-inflammatory (M1) to a pro-repair (M2) phenotype. In conclusion, both DSCs and ASCs were able to accelerate the healing of mice skin wounds and promote repair with scars of better quality and more similar to healthy skin than the empty scaffold. DSCs associated with Integra induced superior overall results than the Integra alone, whereas scaffolds with ASCs showed an intermediate effect, often not significantly better than the empty biomaterial.

FGF2 Stimulates the Growth and Improves the Melanocytic Commitment of Trunk Neural Crest Cells.

Neural crest cells (NCCs) comprise a population of multipotent progenitors and stem cells at the origin of the peripheral nervous system (PNS) and melanocytes of skin, which are profoundly influenced by microenvironmental factors, among which is basic fibroblast growth factor 2 (FGF2). In this work, we further investigated the role of this growth factor in quail trunk NC morphogenesis and demonstrated its huge effect in NCC growth mainly by stimulating cell proliferation but also reducing cell death, despite that NCC migration from the neural tube explant was not affected. Moreover, following FGF2 treatment, reduced expression of the early NC markers Sox10 and FoxD3 and improved proliferation of HNK1-positive NCC were observed. Since these markers are involved in the regulation of glial and melanocytic fate of NC, the effect of FGF2 on NCC differentiation was investigated. Therefore, in the presence of FGF2, increased proportions of NCCs positives to the melanoblast marker Mitf as well as NCCs double stained to Mitf and BrdU were recorded. In addition, treatment with FGF2, followed by differentiation medium, resulted in increased expression of melanin and improved proportion of melanin-pigmented melanocytes without alteration in the glial marker Schwann myelin protein (SMP). Taken together, these data further reveal the important role of FGF2 in NCC proliferation, survival, and differentiation, particularly in melanocyte development. This is the first demonstration of FGF2 effects in melanocyte commitment of NC and in the proliferation of Mitf-positive melanoblasts. Elucidating the differentiation process of embryonic NCCs brings us a step closer to understanding the development of the PNS and then undertaking the search for advanced technologies to prevent, or treat, injuries caused by NC-related disorders, also known as neurocristopathies.

Human Dental Pulp Stem Cells in Rat Mandibular Bone Defects.

This study aimed to evaluate the use of human dental pulp stem cells (hDPSCs) in non-critical-sized mandibular bone defects in rats. hDPSCs from permanent teeth were isolated and engrafted in mandibular bone defects in rats for 7, 14, and 28 days; bone defects without cells formed the control group. Samples were evaluated by scanning electron microscopy (SEM), light microscopy (hematoxylin and eosin staining), and the regeneration area was measured by the Image J program. Before surgery procedures, the human dental pulp cells were characterized as dental pulp stem cells: fusiform morphology, plastic-adherent; expression of CD105, CD73, and CD90; lack of expression of CD45 and CD34, and differentiated into osteoblasts, adipocytes, and chondroblasts. The results indicated that within 7 days the control group presented a pronounced bone formation when compared with the treated group (p < 0.05). After 14 days, the treated group showed an increase in bone formation, but with no statistical difference among the groups (p > 0.05). In the final evaluated period there was no difference between the control group and the treated group (p > 0.05). There was a significant difference between 7 and 14 days (p < 0.05) and between 7 and 28 days (p < 0.05) in the treated group. In conclusion, there is no evidence that the use of hDPSCs in the conditions of this study could improve bone formation in non-critical-sized mandibular bone defects.

Effects of Folic Acid and Homocysteine on the Morphogenesis of Mouse Cephalic Neural Crest Cells In Vitro.

Folate deficiency and hyperhomocysteinemia have long been associated with developmental anomalies, particularly neural tube defects and neurocristopathies-a group of diverse disorders that result from defective growth, differentiation, and migration of neural crest (NC) cells. However, the exact mechanisms by which homocysteine (Hcys) and/or folate deficiencies disrupt NC development are still poorly understood in mammals. In this work, we employed a well-defined culture system to investigate the effects of Hcys and folic acid (FA) supplementation on the morphogenetic processes of murine NC cells in vitro. We demonstrated that Hcys increases outgrowth and proliferation of cephalic NC cells and impairs their differentiation into smooth muscle cells. In addition, we showed that FA alone does not directly affect the developmental dynamics of the cephalic NC cells but is able to prevent the Hcys-induced effects. Our results, therefore, suggest that elevated Hcys levels per se cause dysmorphogenesis of the cephalic NC and might contribute to neurocristopathies in mammalian embryos.

Transplantation of Human Skin-Derived Mesenchymal Stromal Cells Improves Locomotor Recovery After Spinal Cord Injury in Rats.

Spinal cord injury (SCI) is a devastating neurologic disorder with significant impacts on quality of life, life expectancy, and economic burden. Although there are no fully restorative treatments yet available, several animal and small-scale clinical studies have highlighted the therapeutic potential of cellular interventions for SCI. Mesenchymal stem cells (MSCs)-which are conventionally isolated from the bone marrow-recently emerged as promising candidates for treating SCI and have been shown to provide trophic support, ameliorate inflammatory responses, and reduce cell death following the mechanical trauma. Here we evaluated the human skin as an alternative source of adult MSCs suitable for autologous cell transplantation strategies for SCI. We showed that human skin-derived MSCs (hSD-MSCs) express a range of neural markers under standard culture conditions and are able to survive and respond to neurogenic stimulation in vitro. In addition, using histological analysis and behavioral assessment, we demonstrated as a proof-of-principle that hSD-MSC transplantation reduces the severity of tissue loss and facilitates locomotor recovery in a rat model of SCI. Altogether, the study provides further characterization of skin-derived MSC cultures and indicates that the human skin may represent an attractive source for cell-based therapies for SCI and other neurological disorders. Further investigation is needed to elucidate the mechanisms by which hSD-MSCs elicit tissue repair and/or locomotor recovery.

EGF-FGF2 stimulates the proliferation and improves the neuronal commitment of mouse epidermal neural crest stem cells (EPI-NCSCs).

Epidermal neural crest stem cells (EPI-NCSCs), which reside in the bulge of hair follicles, are attractive candidates for several applications in cell therapy, drug screening and tissue engineering. As suggested remnants of the embryonic neural crest (NC) in an adult location, EPI-NCSCs are able to generate a wide variety of cell types and are readily accessible by a minimally invasive procedure. Since the combination of epidermal growth factor (EGF) and fibroblast growth factor type 2 (FGF2) is mitogenic and promotes the neuronal commitment of various stem cell populations, we examined its effects in the proliferation and neuronal potential of mouse EPI-NCSCs. By using a recognized culture protocol of bulge whiskers follicles, we were able to isolate a population of EPI-NCSCs, characterized by the migratory potential, cell morphology and expression of phenotypic markers of NC cells. EPI-NCSCs expressed neuronal, glial and smooth muscle markers and exhibited the NC-like fibroblastic morphology. The treatment with the combination EGF and FGF2, however, increased their proliferation rate and promoted the acquisition of a neuronal-like morphology accompanied by reorganization of neural cytoskeletal proteins ßIII-tubulin and nestin, as well as upregulation of the pan neuronal marker ßIII-tubulin and down regulation of the undifferentiated NC, glial and smooth muscle cell markers. Moreover, the treatment enhanced the response of EPI-NCSCs to neurogenic stimulation, as evidenced by induction of GAP43, and increased expression of Mash-1 in neuron-like cell, both neuronal-specific proteins. Together, the results suggest that the combination of EGF-FGF2 stimulates the proliferation and improves the neuronal potential of EPI-NCSCs similarly to embryonic NC cells, ES cells and neural progenitor/stem cells of the central nervous system and highlights the advantage of using EGF-FGF2 in neuronal differentiation protocols.

Evaluation of secretomes derived from human dermal and adipose tissue mesenchymal stem/stromal cells for skin wound healing: not as effective as cells.

BACKGROUND: Although the paracrine effects of mesenchymal stem/stromal cells (MSCs) have been recognized as crucial mediators of their regenerative effects on tissue repair, the potential of MSC secretomes as effective substitutes for cellular therapies remains underexplored. METHODS: In this study, we compared MSCs from the human dermis (DSCs) and adipose tissue (ASCs) with their secretomes regarding their efficacy for skin wound healing using a translationally relevant murine model. RESULTS: Proteomic analysis revealed that while there was a substantial overlap in protein composition between DSC and ASC secretomes, specific proteins associated with wound healing and angiogenesis were differentially expressed. Despite a similar angiogenic potential in vivo, DSC and ASC secretomes were found to be less effective than cells in accelerating wound closure and promoting tissue remodeling. CONCLUSIONS: Overall, secretome-treated groups showed intermediary results between cells- and control-treated (empty scaffold) groups. These findings highlight that although secretomes possess therapeutic potential, their efficacy might be limited compared to cellular therapies. This study contributes to the growing understanding of MSC secretomes, emphasizes the need for further protocol optimization, and offers insights into their potential applications in regenerative medicine.

Flavonoid hesperidin protects neural crest cells from death caused by aflatoxin B(1).

The neural crest (NC) corresponds to a collection of multipotent and oligopotent progenitors endowed with both neural and mesenchymal potentials. The derivatives of the NC at trunk level include neurons and glial cells of the peripheral nervous system. Despite the well-known influence of aflatoxins on the development of cancer, the issue of whether they also influence NC cells has not been yet addressed. In the present work, we have investigated the effects of aflatoxin B(1) on quail NC cells and the concomitant effects of the flavonoid hesperidin associated with this mycotoxin. We show for the first time that aflatoxin B(1) decreases the viability and the total number of glial and neuronal cells/field, although their proportions in relation to the total number of cells were not altered. Therefore, aflatoxin has no effect on NC differentiation. However, this compound was able to reduce NC proliferation and NC survival. Furthermore, the co-administration of hesperidin, a well-known polyphenolic protector of cell death, partially prevented the effect of aflatoxin B(1) . Taken together, our results demonstrate that aflatoxin B(1) is toxic to NC cells, an effect partially prevented by the flavonoid hesperidin. This study may contribute to the understanding of the effects of these compounds during early embryonic development and offer potentially more assertive diets and treatments for pregnant animals.

The flavonoids hesperidin and rutin promote neural crest cell survival.

The neural crest (NC) corresponds to a collection of multipotent and oligopotent progenitors endowed with both neural and mesenchymal potentials. The derivatives of the NC at trunk level include neurons and glial cells of the peripheral nervous system in addition to melanocytes, smooth muscle cells and some endocrine cells. Environmental factors control the fate decisions of NC cells. Despite the well-known influence of flavonoids on the central nervous system, the issue of whether they also influence NC cells has not been yet addressed. Flavonoids are polyphenolic compounds that are integral components of the human diet. The biological activities of these compounds cover a very broad spectrum, from anticancer and antibacterial activities to inhibition of bone reabsorption and modulation of inflammatory response. In the present work, we have investigated the actions of the flavonoids hesperidin, rutin and quercetin on NC cells of quail, in vitro. We show for the first time, that hesperidin and rutin increase the viability of trunk NC cells in culture, without affecting cell differentiation and proliferation. The molecular mechanism of this action is dependent on ERK2 and PI3K pathways. Quercetin had no effect on NC progenitors. Taken together, these results suggest that flavonoids hesperidin and rutin increase NC cell survival, which may be useful against the toxicity of some chemicals during embryonic development.

Fibroblast growth factor-2 bound to specific dermal fibroblast-derived extracellular vesicles is protected from degradation.

Fibroblast growth factor-2 (FGF2) has multiple roles in cutaneous wound healing but its natural low stability prevents the development of its use in skin repair therapies. Here we show that FGF2 binds the outer surface of dermal fibroblast (DF)-derived extracellular vesicles (EVs) and this association protects FGF2 from fast degradation. EVs isolated from DF cultured in the presence of FGF2 harbor FGF2 on their surface and FGF2 can bind purified EVs in absence of cells. Remarkably, FGF2 binding to EVs is restricted to a specific subpopulation of EVs, which do not express CD63 and CD81 markers. Treatment of DF with FGF2-EVs activated ERK and STAT signaling pathways and increased cell proliferation and migration. Local injection of FGF2-EVs improved wound healing in mice. We further demonstrated that binding to EVs protects FGF2 from both thermal and proteolytic degradation, thus maintaining FGF2 function. This suggests that EVs protect soluble factors from degradation and increase their stability and half-life. These results reveal a novel aspect of EV function and suggest EVs as a potential tool for delivering FGF2 in skin healing therapies.

Administration of mesenchymal stem cells from adipose tissue at the hip joint of dogs with osteoarthritis: A systematic review.

This systematic review aimed to determine the effects of intra-articular administration of mesenchymal stem cells from adipose tissue in dogs with hip joint osteoarthritis (OA). Clinical trials were systematically reviewed, using PubMed, EMBASE, Cochrane Library, LILACS, Web of Science, Scopus, Open Grey, Google Scholar, and ProQuest Dissertation and Thesis without publication year restrictions. References were screened and selected based on predefined eligibility criteria by two independent reviewers, according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Clinical outcomes were assessed quantitatively using clinical pain scores, physical examination, imaging examination, questionnaire responses, pain in manipulation, gait analysis, range of joint motion, and adverse effects. The risk of bias was assessed using the Joanna Briggs Institute Critical Appraisal Checklist. Out of 1483 articles, six met the inclusion criteria for qualitative analysis, with two randomized controlled trials and four before-and-after studies. All studies reported significantly better clinical outcomes in the adipose tissue stem cells (ADSC) group with improvements in pain and function and decreased evidence of hip OA. The risk of bias was categorized as high in the before-and-after studies and moderate to high in the randomized studies. The studies were considered heterogeneous owing to clinical results and methodology. Because of this heterogeneity, it was not possible to perform meta-analysis. Assessments of ADSC reports yielded positive clinical effects that showed improvements in pain and function and decreased evidence of hip osteoarthritis. More high-level, larger-cohort dog studies that utilize standardized protocols are needed.

Impaired astrocytic extracellular matrix distribution under congenital hypothyroidism affects neuronal development in vitro.

Astrocytes clearly play a role in neuronal development. An indirect mechanism of thyroid hormone (T3) in the regulation of neuronal development mediated by astrocytes has been proposed. T3 alters the production and organization of the extracellular matrix (ECM) proteins and proteoglycans, producing a high-quality substrate for neuronal differentiation. The present study investigated the effect of hypothyroidism on the astrocyte production of fibronectin (FN) and laminin (LN) as well as their involvement in neuronal growth and neuritogenesis. Our results demonstrated that the amount of both FN and LN were significantly reduced in cultures of hypothyroid astrocytes from rat cerebellum compared with normal cells. This effect was accompanied by reduced numbers of neurons and neuritogenesis. Similarly, the proportions of neurons and neurons with neurites were reduced in cultures on ECM prepared from hypothyroid astrocytes in comparison with normal cells. The proportion of both normal and hypothyroid neurons is strongly reduced in astrocyte ECM compared with cocultures on astrocyte monolayers, suggesting that extracellular factors other than ECM proteins are involved in this process. Moreover, treatment of hypothyroid astrocytic cultures with T3 restored the area of both FN and LN immunostaining to normal levels and partially reestablished neuronal survival and neuritogenesis. Taken together, our results demonstrated that hypothyroidism involves impairment of the astrocytic microenvironment and affects the production of ECM proteins. Thus, hypothyroidism is implicated in impaired neuronal development.

Fibronectin promotes differentiation of neural crest progenitors endowed with smooth muscle cell potential.

The neural crest (NC) is a model system used to investigate multipotency during vertebrate development. Environmental factors control NC cell fate decisions. Despite the well-known influence of extracellular matrix molecules in NC cell migration, the issue of whether they also influence NC cell differentiation has not been addressed at the single cell level. By analyzing mass and clonal cultures of mouse cephalic and quail trunk NC cells, we show for the first time that fibronectin (FN) promotes differentiation into the smooth muscle cell phenotype without affecting differentiation into glia, neurons, and melanocytes. Time course analysis indicated that the FN-induced effect was not related to massive cell death or proliferation of smooth muscle cells. Finally, by comparing clonal cultures of quail trunk NC cells grown on FN and collagen type IV (CLIV), we found that FN strongly increased both NC cell survival and the proportion of unipotent and oligopotent NC progenitors endowed with smooth muscle potential. In contrast, melanocytic progenitors were prominent in clonogenic NC cells grown on CLIV. Taken together, these results show that FN promotes NC cell differentiation along the smooth muscle lineage, and therefore plays an important role in fate decisions of NC progenitor cells.

Epidermal growth factor (EGF) promotes the in vitro differentiation of neural crest cells to neurons and melanocytes.

Proliferation of neural crest (NC) stem cells and their subsequent differentiation into different neural cell types are key early events in the development of the peripheral nervous system. Soluble growth factors present at the sites where NC cells migrate are critical to the development of NC derivatives in each part of the body. In the present study, we further investigate the effect of microenvironmental factors on quail trunk NC development. We show for the first time that EGF induces differentiation of NC to the neuronal and melanocytic phenotypes, while fibroblast growth factor 2 (FGF2) promotes NC differentiation to Schwann cells. In the presence of both EGF and FGF2, the neuronal differentiation predominates. Our results suggest that FGF2 stimulates gliogenesis, while EGF promotes melanogenesis and neurogenesis. The combination of both growth factors stimulates neurogenesis. These findings suggest that these two growth factors may play an important role in the fate decision of NC progenitors and in the development of the peripheral nervous system.

In vitro comparative study of human mesenchymal stromal cells from dermis and adipose tissue for application in skin wound healing.

Novel strategies combining cell therapy, tissue engineering, and regenerative medicine have been developed to treat major skin wounds. Although mesenchymal stromal cells (MSCs) from different tissues have similar stem cell features, such as self-renewing mesodermal differentiation potential and expression of immunophenotypic markers, they also have distinct characteristics. Therefore, we aimed to characterize the application of MSCs derived from the dermis and adipose tissue (DSCs and ASCs, respectively) in cutaneous wound healing by in vitro approaches. Human DSC and ASC were obtained and evaluated for their isolation efficiency, stemness, proliferative profile, and genetic stability over time in culture. The ability of wound closure was first assessed by direct cell scratch assay. The paracrine effects of DSC- and ASC-conditioned medium in dermal fibroblasts and keratinocytes and in the induction of tubule formation were also investigated. Although the ASC isolation procedures resulted in 100 times more cells than DSC, the latter had a higher proliferation rate in culture. Both presented low frequency of nuclear alterations over time in culture and showed similar characteristics of stem cells, such as expression of immunophenotypic markers and differentiation potential. DSCs showed increased healing capacity, and their conditioned media had greater paracrine effect in closing the wound of dermal fibroblasts and keratinocytes and in inducing angiogenesis. In conclusion, the therapeutic potential of MSCs is influenced by the obtainment source. Both ASCs and DSCs are applicable for skin wound healing; however, DSCs have an improved potential and should be considered for future applications in cell therapy.

Thyroid hormone increases astrocytic glutamate uptake and protects astrocytes and neurons against glutamate toxicity.

Thyroid hormone (T(3)) regulates the growth and differentiation of rat cerebellar astrocytes. Previously, we have demonstrated that these effects are due, at least in part, to the increased expression of extracellular matrix molecules and growth factors, such as fibroblast growth factor-2. T(3) also modulates neuronal development in an astrocyte-mediated manner. In the mammalian central nervous system, excitatory neurotransmission is mediated mainly by glutamate. However, excessive stimulation of glutamate receptors can lead to excitotoxicity and cell death. Astrocytic glutamate transporters, GLT-1 and GLAST, play an essential role in the clearance of the neuronal-released glutamate from the extracellular space and are essential for maintaining physiological extracellular glutamate levels in the brain. In the present study, we showed that T(3) significantly increased glutamate uptake by cerebellar astrocytes compared with control cultures. Inhibitors of glutamate uptake, such as L-PDC and DL-TBOA, abolished glutamate uptake on control or T(3)-treated astrocytes. T(3) treatment of astrocytes increased both mRNA levels and protein expression of GLAST and GLT-1, although no significant changes on the distribution of these transporters were observed. The gliotoxic effect of glutamate on cultured cerebellar astrocytes was abolished by T(3) treatment of astrocytes. In addition, the neuronal viability against glutamate challenge was enhanced on T(3)-treated astrocytes, showing a putative neuroprotective effect of T(3). In conclusion, our results showed that T(3) regulates extracellular glutamate levels by modulating the astrocytic glutamate transporters. This represents an important mechanism mediated by T(3) on the improvement of astrocytic microenvironment in order to promote neuronal development and neuroprotection.

Is there a role for fibronectin upon true histiocytic lymphoma progression?

Cell interaction with extracellular matrix is a crucial event for various biological processes, including tumor progression. Although not exclusively, these interactions are frequently mediated by bidirectional signaling receptors known as integrins. Using a human histiocytic lymphoma-derived cell line (U-937), we evaluated the effects of ECM proteins and their integrin-type receptors in the regulation of cell attachment, proliferation, migration and survival. Fibronectin induces higher cell attachment in vitro when compared to laminin. Fibronectin also promotes a decrease in cell migration but do not modulate cell proliferation and death. Pre-incubation of U-937 cells with VLA-5 antagonistic peptides inhibited attachment of the cells to fibronectin-coated substrates. In a second vein, we observed that lymph node specimens obtained from diagnosed patient for true histiocytic lymphoma had greater deposition of fibronectin (but not laminin) around malignant clones. These results suggest that fibronectins play a relevant role in the establishment and progression of true histiocytic lymphoma cells.