• Cryopreservation
• Graphene oxide
• Human adipose stem cell

• Cryopreservation/methods
• Humans
• Animals
• Adipose Tissue/cytology
• Stem Cells/cytology
• Stem Cells/drug effects
• Cell Survival/drug effects
• Cryoprotective Agents/pharmacology
• Mice, Nude
• Cell Differentiation/drug effects
• Apoptosis/drug effects
• Adipocytes/cytology
• Adipocytes/drug effects
• Mice
• Cell Proliferation/drug effects
• Cells, Cultured
• Graphite

• 2017-I2M-3-006 the CAMS Initiation Fund for Medical Sciences

• Animals
• Mice
• Bone Marrow
• Mice, Inbred BALB C
• Burns
• Wound Healing
• Platelet-Rich Plasma

• MSCs
• bone fracture
• immune cells

• Humans
• Osteogenesis/physiology
• Reproducibility of Results
• Bone and Bones
• Fractures, Bone/therapy
• Mesenchymal Stem Cells/physiology
• Mesenchymal Stem Cell Transplantation
• Fracture Healing/physiology

• 32072806 and 32002246 National Natural Science Foundation of China
• 2019TD-036 Program of Shaanxi Province Science and Technology Innovation Team
• 2022NY-044 Program of Shaanxi Province Science and Technology

• Aryl hydrocarbon receptor
• Bone marrow mesenchymal stromal cells
• Interaction
• Macrophage
• Osteogenesis
• Signal transducer and activator of transcription 3

• extracellular vesicles
• inflammaging
• macrophages
• mesenchymal stromal cells

Mesenchymal stem cells (MSCs) are known to be able to modulate immune responses, possess tissue-protective properties, and exhibit healing capacities with therapeutic potential for various diseases. The ability of MSCs to secrete various cytokines and growth factors provides new insights into autoimmune-diseases such as rheumatoid arthritis (RA). RA is a systemic autoimmune disease that affects the lining of synovial joints, causing stiffness, pain, inflammation, and joint erosion. In recent years, MSCs-based therapies have been widely proposed as promising therapies in the treatment of RA. However, the mechanism involved in disease-specific therapeutic effects of MSCs on RA remains unclear. To clarify the mechanism involved in effects of MSCs on RA, proteomic profiling was performed using an RA mouse model before and after treatment with MSCs. In this study, treatment efficacy of human umbilical cord blood-mesenchymal stem cells (hUCB-MSCs) was confirmed using a type II collagen-induced arthritis (CIA) mouse model. Results of measuring incidence rates of arthritis and clinical arthritis index (CAI) revealed that mice administrated with hUCB-MSCs had a significant reduction in arthritis severity. Proteins that might affect disease progression and therapeutic efficacy of hUCB-MSC were identified through LC-MS/MS analysis using serum samples. In addition, L-1000 analysis was performed for hUCB-MSC culture medium. To analysis data obtained from LC–MS/MS and L-1000, tools such as ExDEGA, MEV, and DAVID GO were used. Results showed that various factors secreted from hUCB-MSCs might play roles in therapeutic effects of MSCs on RA, with platelet activation possibly playing a pivotal role. Results of this study also suggest that SERPINE1 and THBS1 among substances secreted by hUCB-MSC might be key factors that can inhibit platelet activation. This paper is expected to improve our understanding of mechanisms involved in treatment effects of stem cells on rheumatoid arthritis.

• Mice
• Humans
• Animals
• Mesenchymal Stem Cell Transplantation
• Proteomics
• Chromatography, Liquid
• Tandem Mass Spectrometry
• Mesenchymal Stem Cells
• Arthritis, Rheumatoid
• Disease Models, Animal

• the Korea Health Industry Development Institute (KHIDI), Ministry of Health and Welfare

• BMSCs
• Biomaterial
• Inflammation
• Macrophages
• Tissue regeneration

• Biphasic calcium phosphate
• Critical-sized bone defects
• Innate immune response
• Mesenchymal stromal cells
• Monocyte-macrophages
• Neutrophils
• Osteogenesis

• Animals
• Bone Regeneration
• Humans
• Hydroxyapatites
• Immunity, Innate
• Mesenchymal Stem Cells/metabolism
• Rats
• Rats, Inbred Lew

• Immunomodulatory
• Macrophages
• Mesenchymal stem cells
• Osteogenesis
• Titanium-based implants

• arteriovenous (AV) bundle
• avascular necrosis of bone
• fetal bovine serum
• platelet-rich plasma
• stromal vascular fraction

• bone fracture
• mesenchymal stem cells
• osteoporosis
• targeted cell delivery

Transplantation of mesenchymal stem cells (MSCs) has been considered an effective therapeutic treatment for a variety of diseases including bone fracture. However, there are associated complications along with MSCs transplantation. There is evidence to show that exosomes (Exos) derived from MSCs exert a similar paracrine function. In addition, repair capabilities of MSCs decline with age. Hence, this study aims to confirm whether the Exos protective function on osteogenic differentiation and fracture healing from aged MSCs was attenuated. This information was used in order to investigate the underlying mechanism. MSCs were successfully isolated and identified from young and aged rats, and Exos were then obtained. Aged-Exos exhibited significantly attenuated effects on MSCs osteogenic differentiation in vitro and facture healing in vivo. Using miRNA array analysis, it was shown that miR-128-3p was markedly upregulated in Aged-Exos. In vitro experiments confirmed that Smad5 is a direct downstream target of miR-128-3p, and was inhibited by overexpressed miR-128-3p. A series gain- and loss- function experiment indicated that miR-128-3P serves a suppressor role in the process of fracture healing. Furthermore, effects caused by miR-128-3P mimic/inhibitor were reversed by the application of Smad5/siSmad5. Taken together, these results suggest that the therapeutic effects of MSCs-derived Exos may vary according to differential expression of miRNAs. Exosomal miR-128-3P antagomir may act as a promising therapeutic strategy for bone fracture healing, especially for the elderly.

• Bone fracture
• Exosomes
• Mesenchymal stem cells
• Smad5
• miR-128-3P

Cells, scaffolds, and factors are the triad of regenerative engineering; however, it is difficult to distinguish whether cells in the regenerative construct are from the seeded cells or host cells via the host blood supply. We performed a novel in vivo study to transplant enhanced green fluorescent pig mesenchymal stem cells (EGFP-pMSCs) into calvarial defect of DsRed pigs. The cell distribution and proportion were distinguished by the different fluorescent colors through the whole regenerative period.

Eight adult domestic Ds-Red pigs were treated with five modalities: empty defects without scaffold (group 1); defects filled only with scaffold (group 2); defects filled with osteoinduction medium-loaded scaffold (group 3); defects filled with 5 x 10³ cells/scaffold (group 4); and defects filled with 5 x 10⁴ cells/scaffold (group 5). The in vitro cell distribution, morphology, osteogenic differentiation, and fluorescence images of groups 4 and 5 were analyzed. Two animals were sacrificed at 1, 2, 3, and 4 weeks after transplantation. The in vivo fluorescence imaging and quantification data showed that EGFP-pMSCs were represented in the scaffolds in groups 4 and 5 throughout the whole regenerative period. A higher seeded cell density resulted in more sustained seeded cells in bone regeneration compared to a lower seeded cell density. Host cells were recruited by seeded cells if enough space was available in the scaffold. Host cells in groups 1 to 3 did not change from the 1st week to 4th week, which indicates that the scaffold without seeded cells cannot recruit host cells even when enough space is available for cell ingrowth. The histological and immunohistochemical data showed that more cells were involved in osteogenesis in scaffolds with seeded cells.

Our in vivo results showed that more seeded cells recruit more host cells and that both cell types participate in osteogenesis. These results suggest that scaffolds without seeded cells may not be effective in bone transplantation.

• Animals
• Bone Regeneration
• Cells, Cultured
• Green Fluorescent Proteins/analysis
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells/cytology
• Osteogenesis
• Skull/injuries
• Skull/ultrastructure
• Swine
• Tissue Scaffolds/chemistry
• Transplantation, Homologous

• Chang Gung Memorial Hospital, Linkou

• adipose-derived mesenchymal stem cells
• angiogenesis
• immunomodulation
• mussel-inspired surface
• paracrine effect
• polydopamine

• Animals
• Cell Movement/drug effects
• Cell Proliferation/drug effects
• Ceramics/chemistry
• Ceramics/pharmacology
• Guided Tissue Regeneration
• Humans
• Male
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells/chemistry
• Nanostructures/chemistry
• Nanostructures/therapeutic use
• Neovascularization, Pathologic/pathology
• Neovascularization, Pathologic/therapy
• Paracrine Communication/genetics
• Printing, Three-Dimensional
• Rats
• Skin/drug effects
• Skin/injuries
• Skin/pathology
• Tissue Scaffolds/chemistry
• Wound Healing/genetics

Injured blood vessel repair and blood circulation re-establishment are crucial events for tissue repair. We investigated in primary cultures of human umbilical vein endothelial cells (HUVEC), the effects of platelet lysate (PL), a cocktail of factors released by activated platelets following blood vessel disruption and involved in the wound-healing process triggering. PL exerted a protective effect on HUVEC in an inflammatory milieu by inhibiting IL-1α-activated NF-κB pathway and by inducing the secretion of PGE₂, a pro-resolving molecule in the wound microenvironment. Moreover, PL enhanced HUVEC proliferation, without affecting their capability of forming tube-like structures on matrigel, and activated resting quiescent cells to re-enter cell cycle. In agreement with these findings, proliferation-related pathways Akt and ERK_1/2 were activated. The expression of the cell-cycle activator Cyclin D1 was also enhanced, as well as the expression of the High Mobility Group Box-1 (HMGB1), a protein of the alarmin group involved in tissue homeostasis, repair, and remodeling. These in vitro data suggest a possible in vivo contribution of PL to new vessel formation after a wound by activation of cells resident in vessel walls. Our biochemical study provides a rationale for the clinical use of PL in the treatment of wound healing-related pathologies.

• AKT
• ERK
• HMGB-1
• angiogenesis
• endothelial cells
• human umbilical vein endothelial cells (HUVEC), platelet lysate (PL), platelet factors

The effects of immune cells, in particular macrophages, on the behaviour of mesenchymal stromal cells (MSCs) have recently gained much attention for MSCs‐based tissue‐engineered constructs. This study aimed to evaluate the effect of monocytes/macrophages on the osteogenic differentiation of adipose‐derived mesenchymal stromal cells (ADMSCs) in three‐dimensional (3D) cocultures. For this, we cocultured THP‐1 monocytes, M1 macrophages, or M2 macrophages with ADMSCs on 3D poly(lactic‐co‐glycolic) acid (PLGA)/polycaprolactone (PCL) scaffolds using osteogenic medium for up to 42 days. We found that osteogenic differentiation of ADMSCs was inhibited by monocytes and both macrophage subtypes in 3D scaffolds. Furthermore, coculture of monocytes/macrophages with ADMSCs resulted in downregulated secretion of oncostatin M (OSM) and bone morphogenetic protein 2 (BMP‐2) and inhibited expression of osteogenic markers alkaline phosphatase (ALP), bone sialoprotein (BSP), and runt‐related transcription factor 2 (RUNX2). Compared with both macrophage subtypes, monocytes inhibited osteogenic differentiation of ADMSCs more significantly. These data suggest that the mutual interactions between monocytes/macrophages and ADMSCs negatively affect MSC osteogenic differentiation and thus possibly bone healing capacity, which highlights the importance of the micro‐environment in influencing cell‐based constructs to treat bone defects and the potential to improve their performance by resolving the inflammation ahead of treatment.

• 3D
• adipose-derived mesenchymal stromal cells
• coculture
• macrophages
• monocytes
• osteogenic differentiation

• adipogenesis
• mesenchymal stem cells
• platelets
• regenerative medicine
• skin lesions

• Adipose-derived cells
• Bone regeneration
• Easy access cells
• Intraoperative preparation
• Macrophages
• Stromal vascular fraction

• Bone marrow mesenchymal stem cell
• Immunomodulation
• Laponite
• Macrophage
• Osteogenesis

• Animals
• Bone Regeneration
• Cell Line
• Cells, Cultured
• Female
• Guided Tissue Regeneration/methods
• Immunomodulation
• Macrophages/immunology
• Mesenchymal Stem Cells/drug effects
• Mesenchymal Stem Cells/immunology
• Mice
• Osteogenesis
• Rats
• Rats, Sprague-Dawley
• Silicates/pharmacology

• R01 AA020308 NIAAA NIH HHS
• National Natural Science Foundation of China
• Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support
• National Natural Science Foundation of China
• National High Technology Research and Development Program of China

• Bone repair
• Extracellular matrix
• Extracellular vesicles
• Immunomodulation
• Inflammation
• Mesenchymal stem cells
• Paracrine factors
• Regenerative medicine
• Tissue engineering

• Animals
• Bone and Bones/immunology
• Extracellular Matrix/immunology
• Extracellular Vesicles/immunology
• Humans
• Mesenchymal Stem Cells/immunology
• Wound Healing/immunology

The interplay between implants and the recipient immune environment is key to the long-term effectiveness of bone tissue engineering. In this study, we aimed to investigate the mutual effects between macrophages and cartilage templates in the process of subcutaneous osteogenesis. Primary mice bone marrow derived mesenchymal stem cells (BMSCs) were seeded into gelatin sponge and chondrogenically cultured for 4 weeks in vitro to form cartilage templates. The constructs were then implanted subcutaneously in monocyte-depleted mice or normal C57BL/6 mice. Implants harvested at two months showed inferior osteogenic quality in monocyte-depleted mice compared with that of normal mice. In normal mice, the cartilage templates recruited a high ratio of alternatively activated macrophages (CAM or M2) to classically activated macrophages (AAM or M1), compared with empty sponge. In vitro co-culture assay of macrophages with cartilage templates also showed that the cartilage templates polarized macrophages to the M2 phenotype and that these effects were even stronger than those of primary BMSCs. In turn, the co-culture of polarized macrophages with cartilage templates showed that compared to M0 or M2, M1 significantly increased the expressions of osteogenic and angiogenic markers of cartilage templates. These data suggested that macrophages seem to be indispensable in the osteogenesis of cartilage templates and that cartilage templates have a favorable immunomodulatory ability to polarize macrophages to the M2 phenotype. M1 was the contributing phenotype of macrophages that promoted the osteogenesis and angiogenesis of cartilage templates. Macrophages and cartilage templates cooperate to achieve endochondral bone formation.

The interplay between implants and the recipient immune environment is key to the long-term effectiveness of bone tissue engineering.

We examined the hypothesis that substrate microarchitecture regulates the crosstalk between human mesenchymal stem cells (hMSC) and cell types involved in bone regeneration. Compared with polyester flat substrates having uniformly distributed homogenous pores (2D), three-dimensional polystyrene substrates with randomly oriented and interconnected pores of heterogeneous size (3D) stimulated the stromal secretion of IGF-1 while lessened the production of VEGFR-1, MCP-1 and IL-6. The medium conditioned by hMSC cultured in 3D substrates stimulated tube formation by human endothelial cells (hEC) to a higher extent than medium from 2D cultures. 3D co-cultures of hMSC and hEC contained higher secreted levels of IGF-1, EGF and FGF-2 than 2D co-cultures, resulting in increased hEC proliferation and migration. Substrate microarchitecture influenced the secretion of factors related to bone remodeling as the ratio RANKL to OPG, and the levels of M-CSF and IL-6 were higher in 3D co-cultures of hMSC and human osteoblasts (hOB) than in 2D co-cultures. Cytokine microenvironment in 3D co-cultures stimulated osteoblast matrix reorganization while demoted the late steps of osteoblastic maturation. Altogether, data in this study may unveil a new role of scaffold microarchitecture during bone regeneration, as modulator of the paracrine relationships that hMSC establish with hEC and hOB.

• Avascular necrosis
• Axial vascularization
• Osteogenic graft
• Tissue engineering
• Treatment

Although autologous tissue transplantation represents a valid approach for bone repair, it has encountered crucial barriers in therapeutic translation, not least the invasive process necessary for stem cell isolation. In recent years, the scientific community has made significant strides for identifying new treatment options, and great emphasis has been placed on the tight interaction between skeletal and immune system in modulating the outcome of bone repair. Within the context of specific injury environmental cues, the cross talk among inflammatory cells and tissue resident and/or circulating progenitor cells is crucial to finely coordinate repair and remodeling processes. The appropriate modulation of the inflammatory response can now be considered a new trend in the field of regenerative medicine, as it raises the attracting possibility to enhance endogenous progenitor cell functions, finally leading to tissue repair. Therefore, new treatment options have been developed considering the wide spectrum of bone–inflammation interplay, considering in particular the cell intrinsic cues responsible for the modulation of the injured environment. In this review, we will provide a panoramic overview focusing on novel findings developed to uphold endogenous bone repair.

• bone repair
• circulating progenitor cells
• endogenous progenitor cells
• inflammation
• injury microenvironment
• regenerative medicine
• skeletal progenitor cells

• Biomaterial
• Bone tissue engineering
• Cell therapy
• HA/βTCP
• Mesenchymal stem cells
• Tutoplast

• Antigens, Differentiation/biosynthesis
• Calcium Phosphates/chemistry
• Cell Adhesion
• Cell Survival
• Durapatite/chemistry
• Humans
• Insulin-Like Growth Factor I/biosynthesis
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/metabolism
• Osteogenesis
• Paracrine Communication
• RANK Ligand/biosynthesis
• Tissue Scaffolds/chemistry

Traumatic injury or surgical excision of diseased bone tissue usually require the reconstruction of large bone defects unable to heal spontaneously, especially in older individuals. This is a big challenge requiring the development of biomaterials mimicking the bone structure and capable of inducing the right commitment of cells seeded within the scaffold. In particular, given their properties and large availability, the human adipose-derived stem cells are considered as the better candidate for autologous cell transplantation. In order to evaluate the regenerative potential of these cells along with an osteoinductive biomaterial, we have used collagen/hydroxyapatite scaffolds to test ectopic bone formation after subcutaneous implantation in mice. The process was analysed both in vivo, by Fluorescent Molecular Tomography (FMT), and ex vivo, to evaluate the formation of bone and vascular structures. The results have shown that the biomaterial could itself be able of promoting differentiation of host cells and bone formation, probably by means of its intrinsic chemical and structural properties, namely the microenvironment. However, when charged with human mesenchymal stem cells, the ectopic bone formation within the scaffold was increased. We believe that these results represent an important advancement in the field of bone physiology, as well as in regenerative medicine.

• ADMSCs
• Co-culture
• Osteogenic differentiation
• Spheroid

For repair of chronic or difficult-to-heal tissue lesions and defects, major constraints exist to a broad application of cell therapy and tissue engineering approaches, i.e., transplantation of “ex vivo” expanded autologous stem/progenitor cells, alone or associated with carrier biomaterials. To enable a large number of patients to benefit, new strategies should be considered. One of the main goals of contemporary regenerative medicine is to develop new regenerative therapies, inspired from Mother Nature. In all injured tissues, when platelets are activated by tissue contact, their released factors promote innate immune cell migration to the wound site. Platelet-derived factors and factors secreted by migrating immune cells create an inflammatory microenvironment, in turn, causing the activation of angiogenesis and vasculogenesis processes. Eventually, repair or regeneration of the injured tissue occurs via paracrine signals activating, mobilizing or recruiting to the wound site cells with healing potential, such as stem cells, progenitors, or undifferentiated cells derived from the reprogramming of tissue differentiated cells. This review, largely based on our studies, discusses the identification of new tools, inspired by cellular and molecular mechanisms overseeing physiological tissue healing, that could reactivate dormant endogenous regeneration mechanisms lost during evolution and ontogenesis.

• angiogenesis
• cell reprogramming
• innate immunity
• platelet factors
• stem cells
• tissue healing
• tissue regeneration

• Cell culture model
• MSC
• Macrophage
• Osteogenic differentiation

• Adipose Tissue/cytology
• Alkaline Phosphatase/metabolism
• Biomarkers/metabolism
• Calcification, Physiologic
• Cell Communication
• Cell Differentiation/genetics
• Cell Line
• Cell Polarity
• Cell Proliferation
• Coculture Techniques
• Cytokines/metabolism
• Gene Expression Regulation
• Humans
• Macrophages/cytology
• Macrophages/metabolism
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/enzymology
• Osteogenesis/genetics

• 2010622061 China Scholarship Council
• 40-41400-98-1401 ZonMw
• China Scholarship Council

• Cell hypoxia
• Extracellular vesicles
• Inflammation
• Macrophages
• Mesenchymal stem cells
• Regenerative medicine

• Animals
• Anti-Inflammatory Agents/metabolism
• Cell Proliferation/physiology
• Cells, Cultured
• Disease Models, Animal
• Extracellular Vesicles/metabolism
• Flow Cytometry
• Inflammation/metabolism
• Inflammation/therapy
• Macrophages/metabolism
• Macrophages/physiology
• Male
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/metabolism
• Mice
• Mice, Inbred C57BL
• Microscopy, Electron, Transmission
• Real-Time Polymerase Chain Reaction

• Macrophage
• Mesenchymal stem cells
• Oncostatin M
• Osteoblast
• Polarization
• STAT3

• Achilles
• MSC
• TNF-α
• priming
• tendon healing

The concept of pericyte has been changing over years. This cell type was believed to possess only a function of trophic support to endothelial cells and to maintain vasculature stabilization. In the last years, the discovery of multipotent ability of perivascular populations led to the concept of vessel/wall niche. Likewise, several perivascular populations have been identified in animal and human bone marrow. In this review, we provide an overview on bone marrow perivascular population, their cross-talk with other niche components, relationship with bone marrow stromal stem cells, and similarities and differences with the perivascular population of the vessel/wall niche. Finally, we focus on the regenerative potential of these cells and the forthcoming challenges related to their use as cell therapy products.

• CD146
• Nestin
• bone marrow
• endosteal niche
• perivascular cell
• vascular niche

• GFP
• Mesenchymal stem cells
• bone formation
• fluorescence imaging
• transgenic mice

• adult neurogenesis
• brain repair
• mesenchymal stem cells
• neural stem cells
• neurodegenerative diseases
• osteogenesis

Stem and progenitor cells are the critical units for tissue maintenance, regeneration, and repair. The activation of regenerative events in response to tissue injury has been correlated with mobilization of tissue-resident progenitor cells, which is functional to the wound healing process. However, until now there has been no evidence for the presence of cells with a healing capacity circulating in healthy conditions. We identified a rare cell population present in the peripheral blood of healthy mice that actively participates in tissue repair. These Circulating cells, with a Homing ability and involved in the Healing process (CH cells), were identified by an innovative flowcytometry strategy as small cells not expressing CD45 and lineage markers. Their transcriptome profile revealed that CH cells are unique and present a high expression of key pluripotency- and epiblast-associated genes. More importantly, CH-labeled cells derived from healthy Red Fluorescent Protein (RFP)-transgenic mice and systemically injected into syngeneic fractured wild-type mice migrated and engrafted in wounded tissues, ultimately differentiating into tissue-specific cells. Accordingly, the number of CH cells in the peripheral blood rapidly decreased following femoral fracture. These findings uncover the existence of constitutively circulating cells that may represent novel, accessible, and versatile effectors of therapeutic tissue regeneration.

Bone is a unique tissue which could regenerate completely after injury rather than heal itself with a scar. Compared with other tissues the difference is that, during bone repairing and regeneration, after the inflammatory phase the mesenchymal stem cells (MSCs) are recruited to the injury site and differentiate into either chondroblasts or osteoblasts precursors, leading to bone repairing and regeneration. Besides these two precursors, the MSCs can also differentiate into adipocyte precursors, skeletal muscle precursors and some other mesodermal cells. With this multilineage potentiality, the MSCs are probably used to cure bone injury and other woundings in the near future. Here we will introduce the recent developments in understanding the mechanism of MSCs action in bone regeneration and repairing.

Compromised bone-regenerating capability following a long bone fracture is often the result of reduced host bone marrow (BM) progenitor cell numbers and efficacy. Without surgical intervention, these malunions result in mobility restrictions, deformities, and disability. The clinical application of BM-derived mesenchymal stem cells (MSCs) is a feasible, minimally invasive therapeutic option to treat non-union fractures. This review focuses on novel, newly identified cell surface markers in both the mouse and human enabling the isolation and purification of osteogenic progenitor cells as well as their direct and indirect contributions to fracture repair upon administration. Furthermore, clinical success to date is summarized with commentary on autologous versus allogeneic cell sources and the methodology of cell administration. Given our clinical success to date in combination with recent advances in the identification, isolation, and mechanism of action of MSCs, there is a significant opportunity to develop improved technologies for defining therapeutic MSCs and potential to critically inform future clinical strategies for MSC-based bone regeneration.

For a long time, the stem cell regenerative paradigm has been based on the assumption that progenitor cells play a critical role in tissue repair by means of their plasticity and differentiation potential. However, recent works suggest that the mechanism underlying the benefits of stem cell transplantation might relate to a paracrine modulatory effect rather than the replacement of affected cells at the site of injury. Therefore, mounting evidence that stem cells may act as a reservoir of trophic signals released to modulate the surrounding tissue has led to a paradigm shift in regenerative medicine. Attention has been shifted from analysis of the stem cell genome to understanding the stem cell “secretome”, which is represented by the growth factors, cytokines and chemokines produced through paracrine secretion. Insights into paracrine-mediated repair support a new approach in regenerative medicine and the isolation and administration of specific stem cell-derived paracrine factors may represent an extremely promising strategy, introducing paracrine-based therapy as a novel and feasible clinical application. In this review, we will discuss the regenerative potential of fetal and adult stem cells, with particular attention to their secretome.

• microvesicles
• paracrine effect
• secretome
• stem cells
• tissue repair
• trophic factors