Application prospects of urine-derived stem cells in neurological and musculoskeletal diseases

Urine-derived stem cells(USCs)are derived from urine and harbor the potential of proliferation and multidirectional differentiation.Moreover,USCs could be reprogrammed into pluripotent stem cells[namely urine-derived induced pluripotent stem cells(UiPSCs)]through transcription factors,such as octamer binding transcription factor 4,sex determining region Y-box 2,kruppel-like factor 4,myelocytomatosis oncogene,and Nanog homeobox and protein lin-28,in which the first four are known as Yamanaka factors.Mounting evidence supports that USCs and UiPSCs possess high potential of neurogenic,myogenic,and osteogenic differentiation,indicating that they may play a crucial role in the treatment of neurological and musculoskeletal diseases.Therefore,we summarized the origin and physiological characteristics of USCs and UiPSCs and their therapeutic application in neurological and musculoskeletal disorders in this review,which not only contributes to deepen our understanding of hallmarks of USCs and UiPSCs but also provides the theoretical basis for the treatment of neurological and musculoskeletal disorders with USCs and UiPSCs.

Therapeutic potential of urine-derived stem cells in renal regeneration following acute kidney injury:A comparative analysis with mesenchymal stem cells

BACKGROUND Acute kidney injury(AKI)is a common clinical syndrome with high morbidity and mortality rates.The use of pluripotent stem cells holds great promise for the treatment of AKI.Urine-derived stem cells(USCs)are a novel and versatile cell source in cell-based therapy and regenerative medicine that provide advantages of a noninvasive,simple,and low-cost approach and are induced with high multidifferentiation potential.Whether these cells could serve as a potential stem cell source for the treatment of AKI has not been determined.METHODS Stem cell markers with multidifferentiation potential were isolated from human amniotic fluid.AKI severe combined immune deficiency(SCID)mice models were induced by means of an intramuscular injection with glycerol.USCs isolated from human-voided urine were administered via tail veins.The functional changes in the kidney were assessed by the levels of blood urea nitrogen and serum creatinine.The histologic changes were evaluated by hematoxylin and eosin staining and transferase dUTP nick-end labeling staining.Meanwhile,we compared the regenerative potential of USCs with bone marrow-derived mesenchymal stem cells(MSCs).RESULTS Treatment with USCs significantly alleviated histological destruction and functional decline.The renal function was rapidly restored after intravenous injection of 5×105 human USCs into SCID mice with glycerol-induced AKI compared with injection of saline.Results from secretion assays conducted in vitro demonstrated that both stem cell varieties released a wide array of cytokines and growth factors.This suggests that a mixture of various mediators closely interacts with their biochemical functions.Two types of stem cells showed enhanced tubular cell prolif-eration and decreased tubular cell apoptosis,although USC treatment was not more effective than MSC treatment.We found that USC therapy significantly improved renal function and histological damage,inhibited inflammation and apoptosis processes in the kidney,and promoted tubular epithelial proliferation.CONCLUSION Our study demonstrated the potential of USCs for the treatment of AKI,representing a new clinical therapeutic strategy.

Urine-derived stem/progenitor cells:A focus on their characterization and potential

Cell therapy,i.e.,the use of cells to repair an affected tissue or organ,is at the forefront of regenerative and personalized medicine.Among the multiple cell types that have been used for this purpose[including adult stem cells such as mesenchymal stem cells or pluripotent stem cells],urine-derived stem cells(USCs)have aroused interest in the past years.USCs display classical features of mesenchymal stem cells such as differentiation capacity and immunomodulation.Importantly,they have the main advantage of being isolable from one sample of voided urine with a cheap and unpainful procedure,which is broadly applicable,whereas most adult stem cell types require invasive procedure.Moreover,USCs can be differentiated into renal cell types.This is of high interest for renal cell therapy-based regenerative approaches.This review will firstly describe the isolation and characterization of USCs.We will specifically present USC phenotype,which is not an object of consensus in the literature,as well as detail their differentiation capacity.In the second part of this review,we will present and discuss the main applications of USCs.These include use as a substrate to generate human induced pluripotent stem cells,but we will deeply focus on the use of USCs for cell therapy approaches with a detailed analysis depending on the targeted organ or system.Importantly,we will also focus on the applications that rely on the use of USC-derived products such as microvesicles including exosomes,which is a strategy being increasingly employed.In the last section,we will discuss the remaining barriers and challenges in the field of USC-based regenerative medicine.

Extracellular vesicles from human urine-derived stem cells delay aging through the transfer of PLAU and TIMP1

Aging increases the risks of various diseases and the vulnerability to death.Cellular senescence is a hallmark of aging that contributes greatly to aging and aging-related diseases.This study demonstrates that extracellular vesicles from human urine-derived stem cells(USC-EVs)efficiently inhibit cellular senescence in vitro and in vivo.The intravenous injection of USC-EVs improves cognitive function,increases physical fitness and bone quality,and alleviates aging-related structural changes in different organs of senescence-accelerated mice and natural aging mice.The anti-aging effects of USC-EVs are not obviously affected by the USC donors’ages,genders,or health status.Proteomic analysis reveals that USC-EVs are enriched with plasminogen activator urokinase(PLAU)and tissue inhibitor of metalloproteinases 1(TIMP1).These two proteins contribute importantly to the anti-senescent effects of USC-EVs associated with the inhibition of matrix metalloproteinases,cyclin-dependent kinase inhibitor 2A(P16INK4a),and cyclin-dependent kinase inhibitor 1A(P21cip1).These findings suggest a great potential of autologous USC-EVs as a promising anti-aging agent by transferring PLAU and TIMP1 proteins.

A sustained release of BMP2 in urine-derived stemcells enhances the osteogenic differentiation and the potential of bone regeneration

Cell-based tissue engineering is one of the optimistic approaches to replace current treatments for bone defects.Urine-derived stem cells(USCs)are obtained non-invasively and become one of the promising seed cells for bone regeneration.An injectable BMP2-releasing chitosan microspheres/type I collagen hydrogel(BMP2-CSM/Col I hydrogel)was fabricated.USCs proliferated in a time-dependent fashion,spread with good extension and interconnected with each other in different hydrogels both for 2D and 3D models.BMP2 was released in a sustained mode for more than 28 days.Sustained-released BMP2 increased the ALP activities and mineral depositions of USCs in 2D culture,and enhanced the expression of osteogenic genes and proteins in 3D culture.In vivo,the mixture of USCs and BMP2-CSM/Col I hydrogels effectively enhanced bone regeneration,and the ratio of new bone volume to total bone volume was 38%after 8weeks of implantation.Our results suggested that BMP2-CSM/Col I hydrogels promoted osteogenic differentiation of USCs in 2D and 3D culture in vitro and USCs provided a promising cell source for bone tissue engineering in vivo.As such,USCs-seeded hydrogel scaffolds are regarded as an alternative approach in the repair of bone defects.

Urine-derived stem cells:applications in skin,bone and articular cartilage repair

As an emerging type of adult stem cell featuring non-invasive acquisition,urine-derived stem cells(USCs)have shown great potential for applications in tissue engineering and regenerative medicine.With a growing amount of research on the topic,the effectiveness of USCs in various disease models has been shown and the underlying mechanisms have also been explored,though many aspects still remain unclear.In this review,we aim to provide an up-to-date overview of the biological characteristics of USCs and their applications in skin,bone and articular cartilage repair.In addition to the identification procedure of USCs,we also summarize current knowledge of the underlying repair mechanisms and application modes of USCs.Potential concerns and perspectives have also been summarized.

Promotion of right ventricular outflow tract reconstruction using a novel cardiac patch incorporated with hypoxia-pretreated urine-derived stem cells

Approximately 25%of patients with congenital heart disease require implantation of patches to repair.However,most of the currently available patches are made of inert materials with unmatched electrical conductivity and mechanical properties,which may lead to an increased risk for arrhythmia and heart failure.In this study,we have developed a novel Polyurethane/Small intestinal submucosa patch(PSP)with mechanical and electrical properties similar to those of the native myocardial tissue,and assessed its feasibility for the reconstruction of right ventricular outflow tract.A right ventricular outflow tract reconstruction model was constructed in 40 rabbits.Compared with commercially available bovine pericardium patch,the PSP patch has shown better histocompatibility and biodegradability,in addition with significantly improved cardiac function.To tackle the significant fibrosis and relatively poor vascularization during tissue remodeling,we have further developed a bioactive patch by incorporating the PSP composites with urine-derived stem cells(USCs)which were pretreated with hypoxia.The results showed that the hypoxia-pretreated bioactive patch could significantly inhibit fibrosis and promote vascularization and muscularization,resulting in better right heart function.Our findings suggested that the PSP patch combined with hypoxia-pretreated USCs may provide a better strategy for the treatment of congenital heart disease.

Identification and characterization of two morphologically distinct stem cell subpopulations from human urine samples

Urine-derived stem cells(USCs)have shown potentials for the treatment of skeletal and urological disorders.Based on published literature and our own data,USCs consist of heterogeneous populations of cells.In this paper,we identify and characterize two morphologically distinct subpopulations of USCs from human urine samples,named as spindle-shaped USCs(SS-USCs)and rice-shaped USCs(RS-USCs)respectively.The two subpopulations showed similar clone-forming efficiency,while SS-USCs featured faster proliferation,higher motility,and greater potential for osteogenic and adipogenic differentiation,RS-USCs showed greater potential for chondrogenic differentiation.POU5F1 was strongly expressed in both subpopulations,but MYC was weakly expressed.Both subpopulations showed similar patterns of CD24,CD29,CD34,CD44,CD73,CD90 and CD105 expression,while a higher percentage of RS-USCs were positive for CD133.SS-USCs were positive for VIM,weakly positive for SLC12A1 and UMOD,and negative for KRT18,NPHS1,AQP1 and AQP2,indicating a renal mesenchyme origin;while RSUSCs are positive for VIM,partially positive for KRT18,NPHS1,AQP1,SLC12A1 and UMOD,and negative for AQP2,indicating a nephron tubule origin.The above results can facilitate understanding of the biological characteristics of subpopulations of USCs,and provide a basis for further research and applications of such cells.

Matrix from urine stem cells boosts tissue-specific stem cell mediated functional cartilage reconstruction

Articular cartilage has a limited capacity to self-heal once damaged.Tissue-specific stem cells are a solution for cartilage regeneration;however,ex vivo expansion resulting in cell senescence remains a challenge as a large quantity of high-quality tissue-specific stem cells are needed for cartilage regeneration.Our previous report demonstrated that decellularized extracellular matrix(dECM)deposited by human synovium-derived stem cells(SDSCs),adipose-derived stem cells(ADSCs),urine-derived stem cells(UDSCs),or dermal fibroblasts(DFs)provided an ex vivo solution to rejuvenate human SDSCs in proliferation and chondrogenic potential,particularly for dECM deposited by UDSCs.To make the cell-derived dECM(C-dECM)approach applicable clinically,in this study,we evaluated ex vivo rejuvenation of rabbit infrapatellar fat pad-derived stem cells(IPFSCs),an easily accessible alternative for SDSCs,by the abovementioned C-dECMs,in vivo application for functional cartilage repair in a rabbit osteochondral defect model,and potential cellular and molecular mechanisms underlying this rejuvenation.We found that C-dECM rejuvenation promoted rabbit IPFSCs’cartilage engineering and functional regeneration in both ex vivo and in vivo models,particularly for the dECM deposited by UDSCs,which was further confirmed by proteomics data.RNA-Seq analysis indicated that both mesenchymal-epithelial transition(MET)and inflammation-mediated macrophage activation and polarization are potentially involved in the C-dECM-mediated promotion of IPFSCs’chondrogenic capacity,which needs further investigation.