Transforming growth factor-beta (TGF-β)/bone morphogenetic protein (BMP) plays a fundamental role in the regulation of bone organogenesis through the activation of receptor serine/threonine kinases. Perturbations of TGF-β/BMP activity are almost invariably linked to a wide variety of clinical outcomes, i.e., skeletal, extra skeletal anomalies, autoimmune, cancer, and cardiovascular diseases. Phosphorylation of TGF-β (I/II) or BMP receptors activates intracellular downstream Smads, the transducer of TGF-β/BMP signals. This signaling is modulated by various factors and pathways, including transcription factor Runx2. The signaling network in skeletal development and bone formation is overwhelmingly complex and highly time and space specific. Additive, positive, negative, or synergistic effects are observed when TGF-β/BMP interacts with the pathways of MAPK, Wnt, Hedgehog (Hh), Notch, Akt/mTOR, and miRNA to regulate the effects of BMP-induced signaling in bone dynamics. Accumulating evidence indicates that Runx2 is the key integrator, whereas Hh is a possible modulator, miRNAs are regulators, and β-catenin is a mediator/regulator within the extensive intracellular network. This review focuses on the activation of BMP signaling and interaction with other regulatory components and pathways highlighting the molecular mechanisms regarding TGF-β/BMP function and regulation that could allow understanding the complexity of bone tissue dynamics.

BackgroundPrimary mesenchymal stem cells (MSCs) are fraught with aging-related shortfalls. Human-induced pluripotent stem cell (iPSC)-derived MSCs (iMSCs) have been shown to be a useful clinically relevant source of MSCs that circumvent these aging-associated drawbacks. To date, the extent of the retention of aging-hallmarks in iMSCs differentiated from iPSCs derived from elderly donors remains unclear.MethodsFetal femur-derived MSCs (fMSCs) and adult bone marrow MSCs (aMSCs) were isolated, corresponding iPSCs were generated, and iMSCs were differentiated from fMSC-iPSCs, from aMSC-iPSCs, and from human embryonic stem cells (ESCs) H1. In addition, typical MSC characterization such as cell surface marker expression, differentiation capacity, secretome profile, and trancriptome analysis were conducted for the three distinct iMSC preparations—fMSC-iMSCs, aMSC-iMSCs, and ESC-iMSCs. To verify these results, previously published data sets were used, and also, additional aMSCs and iMSCs were analyzed.ResultsfMSCs and aMSCs both express the typical MSC cell surface markers and can be differentiated into osteogenic, adipogenic, and chondrogenic lineages in vitro. However, the transcriptome analysis revealed overlapping and distinct gene expression patterns and showed that fMSCs express more genes in common with ESCs than with aMSCs. fMSC-iMSCs, aMSC-iMSCs, and ESC-iMSCs met the criteria set out for MSCs. Dendrogram analyses confirmed that the transcriptomes of all iMSCs clustered together with the parental MSCs and separated from the MSC-iPSCs and ESCs. iMSCs irrespective of donor age and cell type acquired a rejuvenation-associated gene signature, specifically, the expression of INHBE, DNMT3B, POU5F1P1, CDKN1C, and GCNT2 which are also expressed in pluripotent stem cells (iPSCs and ESC) but not in the parental aMSCs. iMSCs expressed more genes in common with fMSCs than with aMSCs. Independent real-time PCR comparing aMSCs, fMSCs, and iMSCs confirmed the differential expression of the rejuvenation (COX7A, EZA2, and TMEM119) and aging (CXADR and IGSF3) signatures. Importantly, in terms of regenerative medicine, iMSCs acquired a secretome (e.g., angiogenin, DKK-1, IL-8, PDGF-AA, osteopontin, SERPINE1, and VEGF) similar to that of fMSCs and aMSCs, thus highlighting their ability to act via paracrine signaling.ConclusionsiMSCs irrespective of donor age and cell source acquire a rejuvenation gene signature. The iMSC concept could allow circumventing the drawbacks associated with the use of adult MSCs und thus provide a promising tool for use in various clinical settings in the future.Electronic supplementary materialThe online version of this article (10.1186/s13287-019-1209-x) contains supplementary material, which is available to authorized users.

Human amniotic fluid cells are immune-privileged with low immunogenicity and anti-inflammatory properties. They are able to self-renew, are highly proliferative, and have a broad differentiation potential, making them amenable for cell-based therapies. Amniotic fluid (AF) is routinely obtained via amniocentesis and contains heterogeneous populations of foetal-derived progenitor cells including mesenchymal stem cells (MSCs). In this study, we isolated human MSCs from AF (AF-MSCs) obtained during Caesarean sections (C-sections) and characterized them. These AF-MSCs showed typical MSC characteristics such as morphology, in vitro differentiation potential, surface marker expression, and secreted factors. Besides vimentin and the stem cell marker CD133, subpopulations of AF-MSCs expressed pluripotency-associated markers such as SSEA4, c-Kit, TRA-1-60, and TRA-1-81. The secretome and related gene ontology (GO) terms underline their immune modulatory properties. Furthermore, transcriptome analyses revealed similarities with native foetal bone marrow-derived MSCs. Significant KEGG pathways as well as GO terms are mostly related to immune function, embryonic skeletal system, and TGFβ-signalling. An AF-MSC-enriched gene set included putative AF-MSC markers PSG5, EMX-2, and EVR-3. In essence, C-section-derived AF-MSCs can be routinely obtained and are amenable for personalized cell therapies and disease modelling.

Human urine is a non-invasive source of renal stem cells with regeneration potential. Urine-derived renal progenitor cells were isolated from 10 individuals of both genders and distinct ages. These renal progenitors express pluripotency-associated proteins-TRA-1-60, TRA-1-81, SSEA4, C-KIT and CD133, as well as the renal stem cell markers-SIX2, CITED1, WT1, CD24 and CD106. The transcriptomes of all SIX2 + renal progenitors clustered together, and distinct from the human kidney biopsy-derived epithelial proximal cells (hRepcs). Stimulation of the urine-derived renal progenitor cells (UdRpcs) with the GSK3β-inhibitor (CHIR99021) induced differentiation. Transcriptome and KEGG pathway analysis revealed upregulation of Wnt-associated genes-AXIN2, JUN and NKD1. protein interaction network identified JUN-a downstream target of the WNT pathway in association with STAT3, ATF2 and MAPK1 as a putative negative regulator of self-renewal. furthermore, like pluripotent stem cells, self-renewal is maintained by FGF2-driven TGFβ-SMAD2/3 pathway. The urine-derived renal progenitor cells and the data presented should lay the foundation for studying nephrogenesis in human. According to the International Society of Nephrology, more than 850 million people worldwide are afflicted with kidney diseases 1 , which raises the quest for alternative therapies to overcome the limitations associated with current treatments including transplantation and dialysis. One of the most promising options is the utilization of renal stem cells for treating of kidney diseases, disease modelling, and drug development 2,3. Renal stem/ progenitor cells are self-renewing, multipotent cells with the ability to generate various cell types of the kidney to maintain renal function 4. These progenitors are in abundance during fetal kidney development in which the renal progenitor surface marker CD24 and stem cell self-renewal marker CD133 cells are required for primordial nephrogenesis 5,6. However, in adults, CD24, CD133 (Prominin-1) and vascular cell adhesion molecule 1 (CD106)-positive renal progenitors are present in renal tubules and capsules 7. Two progenitor cell populations can be distinguished based on the expression of CD106. For instance, CD24 + CD133 + CD106 − progenitors are present in proximal tubules whereas CD24 + CD133 + CD106 + cells are localized in the Bowman's capsule. The latter can differentiate into a variety of cell types of renal tissue such as podocytes and tubular epithelial cells 4-7. Several groups have identified urine as a non-invasive and repetitive source of renal progenitor cells 8,9. It has been estimated that each day approximately 2,000 to 7,000 cells composed of differentiated epithelial cells, bi-potential epithelial cells (transitional cells), multipotent mesenchymal stem cells, and glomerular parietal cells are flushed out from the renal tubular network and the upper urinary tract into urine 10-12. A subpopulation of these urine-derived cells are renal stem/progenitor cells which express master renal markers such as Sine...

Background Skin burn wound is a notable medical burden worldwide. Rapid and effective treatment of burnt skin is vital to fasten wound closure and healing properly. Amniotic graft and Aloe vera are widely used as wound managing biomaterials. Sophisticated processing, high cost, availability, and the requirement of medics for transplantation limit the application of amnion grafts. We aim to prepare a novel gel from amnion combined with the Aloe vera extract for burn wound healing which overcome the limitations of graft. Methods Two percent human amniotic membrane (AM), Aloe vera (AV) and AM+AV gels were prepared. In vitro cytotoxicity, biocompatibility, cell attachment, proliferation, wound healing scratch assays were performed in presence of the distinct gels. After skin irritation study, second-degree burns were induced on dorsal region of Wistar rats; and gels were applied to observe the healing potential in vivo. Besides, macroscopical measurement of wound contraction and re-epithelialization; gel treated skin was histologically investigated by Hematoxylin and eosin (H&E) staining. Finally, quantitative assessment of angiogenesis, inflammation, and epithelialization was done. Results The gels were tested to be non-cytotoxic to nauplii and compatible with human blood and skin cells. Media containing 500 μg/mL AM+AV gel were observed to promote HaCaT and HFF1 cells attachment and proliferation. In vitro scratch assay demonstrated that AM+AV significantly accelerated wound closure through migration of HaCaT cells. No erythema and edema were observed in skin irritation experiments confirming the applicability of the gels. AV and AM+AV groups showed significantly accelerated wound closure through re-epithelialization and wound contraction with P < 0.01. Macroscopically, AM and AM+AV treated wound recovery rates were 87 and 90% respectively with P < 0.05. Histology analysis revealed significant epitheliazation and angiogenesis in AM+AV treated rats compared to control ( P < 0.05). AM+AV treated wounds had thicker regenerated epidermis, increased number of blood vessels, and greater number of proliferating keratinocytes within the epidermis. Conclusion We demonstrated that a gel consisting of a combination of amnion and Aloe vera extract has high efficacy as a burn wound healing product. Amniotic membrane combined with the carrier Aloe vera in gel format is easy to produce and to apply.