Role of stem cells in kidney repair

End-stage renal disease and acute renal failure are the most important issues of practical and clinical nephrology, bearing in mind their high mortality rate, solely symptomatic treatment, and overall economic impact on society. The advances in stem cell biology opened the door for the new era in treatment of many disorders, including renal, offering new therapeutical solutions. Findings suggesting that the adult kidney contains stem cells and that stem cells from bone marrow have potential to differentiate into renal cells focused research on the possible application of these cells in therapy of kidney disorders. The other promising candidates for stem cell therapy for the kidney are embryonic stem cells and amniotic fluid-derived stem cells. This article focuses on the characteristics and possible application of these types of stem cells.     

Mononuclear phagocyte system in kidney disease and repair

The mononuclear phagocyte system is comprised of circulating monocytes, tissue macrophages and dendritic cells (DCs) that play key roles in tissue homeostasis, immune surveillance, and immune and non‐immune‐mediated tissue injury and repair. This review summarizes the various subsets within this system that exhibit significant functional and phenotypic diversity that can adapt to their surrounding microenvironments during inflammation and in response to colony‐stimulating factor (CSF)‐1. The current understanding of the co‐ordination of monocyte infiltration into the homeostatic and diseased kidney through adhesion molecules, chemokines and chemokine receptors, and cytokines are described. Furthermore, the significant confusion and controversy associated with monocyte differentiation into renal macrophages and DCs following infiltration into the kidney, the considerable functional and phenotypic overlap between both tissue populations and their respective roles in immune and non‐immune‐mediated renal is also discussed. Understanding the factors that control the activation and recruitment of cells from the mononuclear phagocyte system during renal injury may offer an avenue for the development of new cellular and growth factor‐based therapies in combination with existing therapies as an alternative treatment option for patients with renal disease.     

Mesenchymal stem cells: immunobiology and therapeutic potential in kidney disease

SUMMARY: Mesenchymal stem cells (MSC) are non‐haematopoietic cells that are prevalent in the adult bone marrow but can also be isolated from a variety of other postnatal tissues. MSC are non‐immunogenic and are immunosuppressive, with the ability to inhibit maturation of dendritic cells and suppress the function of naïve and memory T cells, B cells and NK cells. In addition to their immunomodulatory properties, MSC are capable of differentiating into various tissues of mesenchymal and non‐mesenchymal origin and migrating to sites of tissue injury and inflammation to participate in tissue repair. A number of studies in animal models of cardiac injury, stroke and ischaemic renal injury have demonstrated the clinical potential of MSC in tissue regeneration and repair. MSC are currently being evaluated in various preclinical and clinical studies in humans and offer significant potential as a novel cellular therapy for tissue regeneration and immunological conditions. The present review focuses on the unique immunomodulatory and regenerative properties of MSC and their potential role in the treatment of kidney disease.     

Adult stem cells in renal injury and repair

There has been considerable focus on the ability of bone marrow-derived cells to differentiate into non-haematopoietic cells of various tissue lineages, including cells of the kidney. This growing evidence has led to a reconsideration of the source of cells contributing to renal repair following injury. The kidney has an inherent ability for recovery and regeneration following acute damage. It is thought that dedifferentiation of glomerular and tubular cells to a more embryonic/mesenchymal phenotype represent key processes for recovery in response to damage. However, there has been much contention as to the source of regenerating renal cells. The present review focuses on new aspects of the plasticity of intrinsic renal cells and their role in renal remodelling and scarring. Growing support also suggests that bone marrow-derived cells have the ability to contribute to structural and functional repair following acute renal failure. Evidence for bone marrow cell engraftment in the repairing kidney leading to incorporation into a variety of tissue types is discussed. Because cell death and fibrosis is a common end-point in a variety of acute and chronic renal nephropathies, the paradigm of stem cell plasticity may have important implications in the cellular and pathological mechanisms of renal injury and repair. A better understanding of the processes controlling extra-renal cell engraftment and intrinsic renal cell differentiation may provide important clues for the development of new cell-based therapies in the field of renal reparative medicine.     

Mesenchymal stem cells and transplant tolerance

Different strategies are being tried to induce transplant tolerance in clinical settings; however, none of them are both safe and effective. Mesenchymal stem cells have been found to be potent immunomodulators and immunosuppressants. We discuss in this review different sources of mesenchymal stem cells and the potent role of adipose tissue‐derived mesenchymal stem cells in induction of transplant tolerance including when to use them and how to use them for achieving the Utopian dream of transplant tolerance.     

Mesenchymal stem cells and bone regeneration: current status

The enhancement of bone regeneration with biological agents including osteogenic growth factors and mesenchymal stem cells (MSCs) is becoming a clinical reality. Many exciting findings have been obtained following MSC implantation in animal models, and the data demonstrating their clinical efficacy in humans are promising. The overwhelming majority of experimental work has been performed with MSCs “amplified” in vitro. The nature of native MSCs in skeletal tissues however, remains poorly understood. This review summarizes recent findings pertaining to the definition and characterisation of MSCs in skeletal tissues and discusses the mechanisms of their actions in regenerating of bone in vivo. In respect to traditional tissue engineering paradigm, we bring together literature showing that the ways MSCs are extracted, expanded and implanted can considerably affect bone formation outcomes. Additionally, we discuss current animal models used in MSC research and highlight recent experiments showing important contribution of the host, and not only donor MSCs, in bone tissue formation. This knowledge provides a platform for novel therapy development for bone regeneration based on pharmacologically manipulated endogenous MSCs.     

In vivo effect of bone marrow‐derived mesenchymal stem cells in a rat kidney transplantation model with prolonged cold ischemia

Brain death and prolonged cold ischemia are major contributors to the poorer long‐term outcome of transplants from deceased donor kidney transplants, with an even higher impact if expanded criteria donors (‘marginal organs’) are used. Targeting ischemia‐reperfusion injury‐related intragraft inflammation is an attractive concept to improve the outcome of those grafts. As mesenchymal stem cells (MSCs) express both immunomodulatory and tissue repair properties, we evaluated their therapeutic efficacy in a rat kidney transplant model of prolonged cold ischemia. The in vitro immunomodulatory capacity of bone marrow‐derived rat MSCs was tested in co‐cultures with rat lymph node cells. For in vivo studies, Dark Agouti rat kidneys were cold preserved and transplanted into Lewis rats. Syngeneic Lewis MSCs were administered intravenously. Transplants were harvested on day 3, and inflammation was examined by quantitative RT‐PCR and histology. Similarly to MSCs from other species, rat MSCs in vitro also showed a dose‐dependent immunomodulatory capacity. Most importantly, in vivo administration of MSCs reduced the intragraft gene expression of different pro‐inflammatory cytokines, chemokines, and intercellular adhesion molecule‐1. In addition, fewer antigen‐presenting cells were recruited into the renal allograft. In conclusion, rat MSCs ameliorate inflammation induced by prolonged cold ischemia in kidney transplantation.     

Muscle-derived stem cells for musculoskeletal tissue regeneration and repair

Muscle recently has been identified as a good source of adult stem cells that can differentiate into cells of different lineages. The most well-known muscle progenitor cells are satellite cells, which not only contribute to the replenishment of the myogenic cell pool but also can become osteoblasts, adipocytes and chondrocytes. Other populations of stem cells that appear to be distinct from satellite cells also have been discovered recently. Muscle-derived stem cells (MDSCs) can be divided into two major categories based on these cells' varied abilities to differentiate into myogenic lineages. Interestingly, MDSCs that can differentiate readily into myogenic cells are usually CD45-. In contrast, MDSCs with less myogenic potential are CD45+. Various lines of evidence suggest that different populations of MDSCs are closely related. Furthermore, MDSCs appear to be closely related to endothelial cells or pericytes of the capillaries surrounding myofibers. When used in tissue engineering applications, MDSCs--particularly those genetically engineered to express growth factors--have been demonstrated to possess great potential for the regeneration and repair of muscle, bone and cartilage. Further research is necessary to delineate the relationship between different populations of MDSCs and between MDSCs and other adult stem cells, to investigate their developmental origin, and to determine the regulatory pathways and factors that control stem cell self-renewal, proliferation and differentiation. This knowledge could greatly enhance the usefulness of muscle-derived stem cells, as well as other adult stem cells, for tissue repair and regeneration applications.     

Mesenchymal stem cells combined with an artificial dermal substitute improve repair in full-thickness skin wounds

Autografts represent the gold standard for the treatment of full thickness burns. Factors such as lack of suitable donor sites and poor skin quality, however, have led to the development of artificial dermal substitutes. The investigation of mechanisms leading to enhanced functionality of these skin substitutes has been attracting great attention. This study aimed to investigate the effect of autologous stem cells on the integration and vascularization of a dermal substitute in full-thickness skin wounds, in a murine model. Two cell populations were compared, whole bone marrow cells and cultivated mesenchymal stem cells, isolated from mice transgenic for the enhanced green fluorescent protein, which allowed tracking of the transplanted cells. The number of cells colonizing the dermal substitute, as well as vascular density, were higher in mice receiving total bone marrow and particularly mesenchymal stem cells, than in control animals. The effect was more pronounced in animals treated with mesenchymal stem cells, which located primarily in the wound bed, suggesting a paracrine therapeutic mechanism. These results indicate that combining mesenchymal stem cells with artificial dermal substitutes may represent an important potential modality for treating full thickness burns, even in allogeneic combinations due to the immunoregulatory property of these cells.     

Hematopoietic stem cell transplantation in patients with chronic kidney disease

Patients with significant medical comorbidities such as chronic kidney disease (CKD) traditionally have been excluded from hematopoietic stem cell transplantation (HSCT) because of unacceptably high transplant-related morbidity and mortality, an exclusion that can have enormous consequences for patients with CKD from myeloma in particular. Much of the excess HSCT-related morbidity among CKD patients relates to the toxic effects of conditioning regimens, which have a narrow therapeutic index even in patients with normal renal function. Common posttransplant complications are more challenging to prevent and manage in patients with CKD. In selected centers, autologous HSCT is performed with some frequency in patients with advanced CKD and even dialysis-dependent end-stage renal disease (ESRD), with acceptable outcomes, but cure from malignancy rarely is obtained. Allogeneic transplants using reduced-intensity conditioning regimens are being used with increasing frequency in patients with CKD, for both nonmalignant and malignant conditions, relying in the latter case on a graft-versus-malignancy effect to eliminate residual malignancy. In patients with ESRD from myeloma who have suitable donors, simultaneous allogeneic HSCT and kidney transplantation from a human leukocyte antigen-identical sibling provides the opportunity to treat both the malignant condition and the ESRD, avoiding the risks of posttransplant care in a dialysis-dependent patient and freeing the patient of the subsequent burdens of both ongoing dialysis and immunosuppression.     

Mouse synovial mesenchymal stem cells increase in yield with knee inflammation

Even though mouse studies have various advantages, harvesting an adequate number of synovial mesenchymal stem cells (MSCs) is difficult in mice. We investigated whether the total yield of MSCs increased in synovium with inflammation in mice. Infrapatellar fat pads (IFPs) were harvested from 10 knees of 5 mice 3, 7, and 14 days after intraarticular injection of carrageenan. Ten IFPs were also harvested from untreated knees as a control. Seven days after initial plating, the total yield of cells was compared among the 4 groups (n = 4–6). The harvested cells were analyzed for multipotentiality and surface epitopes. Furthermore, knee synovitis was compared among the 4 groups in histology. The number of cells in the 3 and 7 days treated group was significantly higher than the other groups. The harvested cells had characteristics of MSCs. Synovitis in the 3 and 7 days treated groups was significantly severer than the other groups. There seemed to be a relationship between the synovitis score and the total yield of cells derived from IFPs. In mice, it became possible to increase the yield 50‐fold by inducing inflammation. This method makes it possible to analyze the molecular mechanisms of cartilage regeneration of synovial MSCs in mice models. © 2014 The Authors. © 2014 The Authors. Journal of Orthopaedic Research published by Wiley Periodicals, Inc. on behalf of the Orthopaedic Research Society. J Orthop Res 33:246–253, 2015.

     

Mesenchymal stem cells are a rescue approach for recovery of deteriorating kidney function

Aim: Stem cell (SC) therapy for chronic kidney disease (CKD) is urgently needed. The use of mesenchymal stem cells (MSC) is a possible new therapeutic modality. Our work aimed to isolate human MSC from adult bone marrow to improve kidney functions in CKD patients. Methods: In our study 30 patients with impaired kidney function were included, their ages ranged from 22 to 68 years. They included 10 inactive glomerulonephritis patients due to systemic lupus erythromatosus (SLE) (group I), 10 renal transplantation cases (group II) and 10 patients of other aetiologies as the control group. Fifty millilitres of bone marrow was aspirated from the iliac bone, for separation of MSC. Results: There was a highly statistically significant difference between both CD271 and CD29 before and after culture with increase of both markers at end of culture, P < 0.01. Finally 50–70 million MSC in 10 mL saline (0.7–1.0 × 10⁶ MSC/kg body weight) were infused intravenously in two divided doses one week apart. There was a highly statistically significant difference between each of serum creatinine and creatinine clearance levels before and after MSC injection at 1, 3 and 6 months post‐infusion with SLE cases showing a greater decline of their serum creatinine and elevation of mean creatinine clearance levels after injection than transplantation and control groups, P < 0.05. Conclusion: Mesenchymal stem cells therapy is a potential therapeutic modality for early phases of CKD.     

Mesenchymal stem cells.

Bone and cartilage formation in the embryo and repair and turnover in the adult involve the progeny of a small number of cells called mesenchymal stem cells. These cells divide, and their progeny become committed to a specific and distinctive phenotypic pathway, a lineage with discrete steps and, finally, end-stage cells involved with fabrication of a unique tissue type, e.g., cartilage or bone. Local cuing (extrinsic factors) and the genomic potential (intrinsic factors) interact at each lineage step to control the rate and characteristic phenotype of the cells in the emerging tissue. The study of these mesenchymal stem cells, whether isolated from embryos or adults, provides the basis for the emergence of a new therapeutic technology of self-cell repair. The isolation, mitotic expansion, and site-directed delivery of autologous stem cells can govern the rapid and specific repair of skeletal tissues.     

Isolation and potential existence of side population cells in adult human kidney

Abstract:   The existence of adult stem-like cells such as side population (SP) cells is reported in various kinds of animal tissues, and we recently reported that mice kidney SP cells differentiate into multilineage. However, there has thus far been no report about human kidney SP cells. In the present study, we examined the existence of SP cells in human kidney tissue by using Hoechst 33342 staining and fluorescence-activated cell sorting analysis. We used porcine kidney tissue to optimize the analysis conditions for human tissue, and found that the SP population in human kidney was 1.3%. The existence of SP cells in human kidney suggests that the cells could be good targets for clinical renal regenerative medicine.     

Renal regeneration after acute kidney injury

Acute kidney injury is common and associated with negative renal and patient outcomes. The human kidney has a real but limited regeneration capacity. Understanding renal regeneration may allow us to manipulate this process and thus develop therapeutic weapons to improve patients’ outcome. In the first part of this paper we discuss the clinical factors associated with renal recovery: baseline patient particularities, acute kidney injury characteristics and the medical approach taken in the short and long‐term. In the second part, the cellular and molecular mechanisms underlying renal regeneration are explored. The immune system seems to have an important role, first promoting inflammation and then tissue healing. Other players, such as cellular senescence, mitochondrial dysfunction, renal haemodynamics and metabolic reprogramming also have a role in renal regeneration. We aim to develop a short review of renal regeneration, offering a holistic view of this process.     

间充质干细胞及其作用的研究新进展

间充质干细胞(MSCs)可以成功地从所有哺乳动物组织细胞内分离出来,它的多向分化潜能在再生医学中有很大应用潜力.随着对MSCs的生物学特征、MSCs与其周围内环境之间的相互作用、MSCs归巢的分子调节机制及多向分化能力的深入研究,MSCs将作为细胞修复或外源性基因转染和表达的载体在临床试验中发挥重要作用.