Mesenchymal stem cells (MSCs) possess pleiotropic properties that include immunomodulation, inhibition of apoptosis, fibrosis and oxidative stress, secretion of trophic factors, and enhancement of angiogenesis. These properties provide a broad spectrum for their potential in a wide range of injuries and diseases, including diabetic nephropathy (DN). MSCs are characterized by adherence to plastic, expression of the surface molecules CD73, CD90, and CD105 in the absence of CD34, CD45, HLA-DR, and CD14 or CD11b and CD79a or CD19 surface molecules, and multidifferentiation capacity in vitro. MSCs can be derived from many tissue sources, consistent with their broad, possibly ubiquitous distribution. This article reviews the existing literature and knowledge of MSC therapy in DN, as well as the most appropriate rodent models to verify the therapeutic potential of MSCs in DN setting. Some preclinical relevant studies are highlighted and new perspectives of combined therapies for decreasing DN progression are discussed. Hence, improved comprehension and interpretation of experimental data will accelerate the progress towards clinical trials that should assess the feasibility and safety of this therapeutic approach in humans. Therefore, MSC-based therapies may bring substantial benefit for patients suffering from DN.
Diabetes mellitus (DM) is a global epidemic disease that affects people of all ages, gender, and ethnicity. The prevalence of DM for all age-groups was estimated to be 2.8% in 2000 and 4.3% in 2030. The total number of people with DM is projected to rise from 171 million in 2000 to 366 million in 2030 according to World Health Organization [
Diabetic nephropathy (DN) is the leading cause of chronic kidney disease in patients starting renal replacement therapy, affecting ~40% of type 1 and type 2 diabetic patients [
Clinical manifestations of DN, such as proteinuria, increased blood pressure, and decreased glomerular filtration rate are similar in type 1 and type 2 diabetes and correlate strongly with structural abnormalities. Morphologically, DN is characterized by thickening of the glomerular basement membrane (GBM) and mesangial expansion, leading to a progressive reduction in the filtration surface of the glomerulus [
Despite the fact that pancreas transplant may reverse the thickness of the glomerular and tubular basement membranes after five years of normoglycemia [
DN progression may be prevented by tight glucose control, blood pressure control, renin-angiotensin-aldosterone system (RAAS) blockade, smoking cessation, weight loss, and physical activity [
To note, mesenchymal stem cell- (MSC-) based therapies have been expected to bring substantial benefit to patients suffering a wide range of diseases and injuries. This article reviews the existing literature and knowledge of MSC therapy in DN and highlights some preclinical relevant studies and new perspectives of combined therapies for decreasing DN progression.
DN is initially characterized by functional glomerular changes, including glomerular hyperperfusion and hyperfiltration, before the onset of any measurable clinical changes. As DN evolves, thickening of the GBM, glomerular hypertrophy, and mesangial expansion take place.
Despite the fact that several factors have been implicated in the pathogenesis of DN, we will focus on the particular factors outlined above [
The early signs of glomerular hyperperfusion and hyperfiltration result from decreased resistance of renal arterioles (afferent > efferent) which are mediated by prostanoids, nitric oxide, vascular endothelial growth factor A (VEGF-A), transforming growth factor-
Hyperglycemia is a key factor in developing DN due to its effect on mesangial cell proliferation, hypertrophy, and apoptosis, as well as an increased matrix production and GBM thickening. These effects are mediated by upregulation of glucose transporters (GLUT1 and GLUT4) and an increase in glucose entrance into the cells.
Hyperglycemia mediates tissue damage by inducing nonenzymatic glycosylation that generates advanced glycosylation end products (AGEs; the cross-link with collagen I contributes to microvascular complications), activation of protein kinase C (PKC; activates vasodilatory prostanoids which contributes to glomerular hyperfiltration, as well as TGF-
Activation of cytokines, profibrotic and inflammatory elements, and vascular growth factors might be involved in the matrix accumulation that takes place in DN. VEGF and angiopoetin contribute to retinopathy, although their effects on DN are not conclusive. To note, VEGF may increase permeability of the glomerular filtration barrier to proteins. Hyperglycemia, TGF-
TGF-
Inflammatory cytokines also contribute to the development and progression of DN, mainly interleukin-1 (IL-1), IL-6, IL-18, and tumor necrosis factor-
Prostaglandin E2 and I2 might promote renal inflammation and renal inhibition of cyclooxygenase 2 is associated with a decrease in glomerular hyperfiltration. Lipoxygenases 12 and 15 are also increased in DN. Furthermore, arachidonic acid oxidation might be related to mesangial cell hypertrophy and extracellular matrix accumulation by TGF-
Reactive oxygen species, generated in the mitochondria, mediate many negative biological effects, including peroxidation of cell membrane lipids, oxidation of proteins, renal vasoconstriction, and damage to DNA, as well as PKC activation and AGEs formation.
In patients with type 1 and type 2 diabetes, the likelihood of developing DN is increased in those who have a sibling or parent with DN. Genotyping single-nucleotide polymorphism investigation indicates that some
MSCs, commonly referred to as mesenchymal stem cells or mesenchymal stromal cells, are a diverse population of cells with a wide range of potential therapeutic applications for different organs and tissues. MSCs can be derived from many tissue sources, consistent with their broad, possibly ubiquitous distribution.
Stem cells are characterized by their ability to self-renew, clone, differentiate into different lineages, and regenerate damaged organ. The International Society for Cell Therapy (ISCT) proposed a criteria to define human (h) MSC that comprises the following: (
Furthermore, murine species obtained from 5 strains were similar to human and rat MSCs in terms of expansion under adherent conditions, single-cell-derived colony formation assay, and multipotent differentiation to osteoblasts, adipocytes, and chondroblasts in vitro [
Historically, MSCs were isolated from bone marrow (BM-MSC) and spleen from guinea pigs by Friedenstein and colleagues [
MSCs can be isolated (a) by using a gradient centrifugation (Ficoll or Percoll) to separate nonnucleated red blood cells from nucleated cells; (b) by taking advantage of their ability to adhere to plastic; or (c) by the ability of monocytes to be separated from MSCs by trypsinization [
During the 1980s, MSCs were shown to differentiate into osteoblasts, chondrocytes, adipocytes, and muscle [
MSCs can be isolated from BM, adipose tissue (ADMSC), umbilical cord blood (UCB-MSC), and other tissues. In BM, 1 in 10,000 nucleated cells is a MSC. To note, one gram of aspirated adipose tissue yields approximately 3.5 × 105–1 × 106 ADMSCs. This is compared to 5 × 102–5 × 104 of BM-MSCs isolated from one gram of bone marrow aspirate [
MSCs possess ubiquitous distribution in perivascular niches and can be derived and propagated in vitro from different organs and tissues (BM, brain, spleen, liver, kidney, lung, muscle, thymus, pancreas, cord blood, amniotic fluid and placental membranes, and large vessels, such as aorta artery and vena cava) [
MSC cell populations originating from different tissues and organs exhibit similar morphology and, to a certain extent, surface marker profile [
Notably, the frequency of MSC engraftment and differentiation in different organs is low compared to the robust functional recovery observed after cell transplant, which has raised questions as to whether MSC engraftment and differentiation is the leading mechanism of action. MSCs secrete a wide array of cytokines and growth factors, which can suppress the immune system, fibrosis oxidative stress, and apoptosis and enhance angiogenesis [
The effects of MSCs on innate and adaptive immunity have been reported in the literature. MSCs modulate the innate function of monocytes, macrophages, natural killer (NK) cells, and dendritic cells (DCs). They are capable of modifying the maturation of DC, thereby inhibiting their antigen-presenting function an inducing the generation of tolerogenic DCs. Importantly, MSCs show intermediate expression of MHC I (Major Complex of Histocompatibility) and do not express MHC II on their surface, which reduces their antigenicity and increases their tolerability in allogeneic transplant [
To note, MSC effect on lymphocytes B cell has been scarcely studied and contradictory, yet it appears that this interaction occurs not only by the modulation of T-helper lymphocyte activity by MSCs, but also by a direct inhibitory mechanism by MSC in B lymphocyte activation [
Although BM-MSCs, ADMSCs, and UCB-MSCs equally hamper T lymphocyte, B lymphocyte, and NK cell-mediated immune response by preventing their acquisition of lymphoblast characteristics, activation, and changing the expression profile of proteins with an important role in immune function, UCB-MSCs do not inhibit B cells activation [
Although these studies suggest that the use of MSCs in regenerative therapies could be successful, the mechanisms responsible for the tolerance of the host immune system to MSCs are not fully understood. Moreover, all these mechanisms are interrelated and involve both direct cell-cell contact and indirect mechanisms, through the production and release of soluble factors, such as cytokines and hormones.
In 2001, the Animal Models of Diabetic Complications Consortium (AMDCC) was created by National Institutes of Health to develop and characterize models of diabetic nephropathy. Hence, AMDCC defined the following criteria for validating a progressive mouse model of DN [
The most promising strains to study DN, in accordance with AMDCC recommendation, include the following: eNOS (endothelial nitric oxide synthase) deficient (C57BL/6 and C57BLKS backgrounds) mice: to generate a model of type 1 DM, streptozotocin (STZ) may be injected and to generate a model of type 2 DM; these mice can be crossed with C57BLKS (BKS)-db/db mice bradykinin B2 receptor deficient (C57BL/6 and C57BLKS backgrounds) mice: these mice can be crossed with decorin (inhibitor of TGF- NONcNZO10/LtJ mice: these mice are derived from a cross between nonobese nondiabetic (NON/lt) strain the New Zealand Obese (NZO/H1Lt) mouse, which provides a model of polygenic type 2 DM) FVB-OVE26 mice (FVB background): transgenic model of early-onset of type 1 DM. Renin overexpression (129S6/SvEvTac background): these mice express plasma renin near eight times normal and develop kidney and cardiovascular disease
Although these transgenic mice develop proteinuria and renal histological abnormalities secondary to DN, they do not reliably develop all of the features of human DN. However, two recent models of type 1 and type 2 diabetes that reflect human DN were reported [
Notably, E1-DN mice were recently described as a model of type 1 diabetes [
The recently described BTBR (black and tan, obese, tufted) ob/ob (leptin deficient) (
To note, pharmacologic induction of DN with STZ, with or without accelerating factors, such as high fat diet, uninephrectomy, or use of the nonobese diabetic strain (NOD) strain has been the most common rodent model of DN to study the potential therapeutic of MSCs [
Yet pharmacological therapy with angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists, glucose and blood pressure control, and lifestyle modifications [
MSCs administration is reported to ameliorate renal and pancreatic parameters in terms of dysfunction and morphological abnormalities, as reported in Table
Preclinical studies in rodents to test the potential of MSCs in DN.
MSC isolation/type of transplant | Model of DN and groups | Number of injections/route of delivery | Number of cells injected | Results | Reference |
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h-BM-MSCs, | STZ-induced type 1 NOD/ | Single dose, | 2.5 × 106 | DN + hMSC versus DN: | [ |
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BM-MSCs, allogeneic | STZ-induced type 1 diabetes C57BL/6 mice: DN + vehicle and DN + MSC | Single dose, | 0.5 × 106 | DN + MSCs versus DN: | [ |
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BM-MSCs, allogeneic | STZ-induced type 1 diabetes C57BL/6 mice: | Two doses (interval of 20 days), | 0.5 × 106 | DN + MSCs versus DN: | [ |
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BM-MSCs, allogeneic | STZ-induced type 1 diabetes Sprague-Dawley Rats: | single dose, intracardiac | 2 × 106 | MSCA group versus DN: | [ |
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ADMSCs, autologous | STZ-induced type 1 diabetes Sprague-Dawley Rats: | Single dose, | 1 × 107 | DN + ADMSCs versus vehicle: | [ |
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h-UCB-SCs, xenotransplant | STZ-induced type 1 diabetes Sprague-Dawley Rats: control, DN, DN + h-UCB-SC | Single dose, | 1 × 106 | DN + h-UCB-SCs versus DN: | [ |
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h-UCB-SCs, xenotransplant | STZ-induced type 1 diabetes Sprague-Dawley Rats: control, DN, DN + h-UCB-SC | Single dose, | 5 × 105 | DN + h-UCB-SCs versus DN: | [ |
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BM-MSCs, allogeneic | STZ-induced type 1 diabetes Sprague-Dawley Rats: Normal control, DN + MSC and DN + medium | Single dose, left renal artery | 2 × 106 | DN + MSCs versus DN + medium: | [ |
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BM-MSCs, allogeneic, UTDM | STZ-induced type 1 diabetes Sprague-Dawley Rats: Normal control, DN + PBS, DN + UTMD, DN + MSC, DN + MSC + UTMD | Single dose, | 1 × 106 | MSC and MSC + UTMD versus DN and UTMD: | [ |
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BM-MSCs, allogeneic | STZ-induced type 1 diabetes Wistar Rats: Normal control, DN + vehicle, DN + MSC | 2 doses | 2 × 106 | DN + MSCs versus DN: | [ |
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BM-MSCs, allogeneic | STZ-induced type 1 diabetes Wistar rats: DN, DN + MSC, DN + Insulin, DN + Probucol | 2 doses | 2 × 106 | DN + MSCs versus DN: | [ |
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BM-MSCs, allogeneic | STZ-induced type 1 diabetes albino rats: Control, DN, DN + PBS, DN + MSC | Single dose, | 1 × 106 | DN + MSCs versus DN: | [ |
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BM-MSCs, allogeneic | Normal control, DN + saline, DN + MSC | 2 doses | 2 × 106 | DN + MSCs versus DN: | [ |
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BM-MSCs, allogeneic | STZ-induced type 1 diabetes Sprague-Dawley Rats: | Single dose, | 1 × 106 | Improvement in renal histology | [ |
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BM-MSCs, allogeneic | STZ-induced type 1 diabetes C57BL/6 mice: DN + vehicle, DN + MSC | Single dose, | 0.5 × 106 | DN + MSCs versus DN: | [ |
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BM-MSCs, allogeneic | STZ-induced type 1 diabetes Sprague-Dawley rats: control, DN, DN + MSC | Single dose, | 2 × 106 | MSCs + DN versus DN: | [ |
MSCs: mesenchymal stem cells; BM-MSC: bone marrow-derived MSCs; h-BM-MSC: human bone marrow-derived MSC; ADMSC: adipose-derived MSCs; h-UCB-SCs: human umbilical cord blood-derived stem cells; DN: diabetic nephropathy; STZ: streptozotocin; CSA: cyclosporine; PBS: phosphate buffered saline; IV: intravenous;
MSCs are generally transient cells that exist briefly in the host and cannot be identified after a few days or possibly a week or two. Their safety as allogeneic cell transplants may be closely related to their short-term existence. Their anti-inflammatory properties, homing to sites of damage and inflammation, and their trophic influence on tissue repair have made them a promising strategy for clinical studies.
Although MSC therapy has already been reported to ameliorate kidney and pancreatic injury, many difficulties must be overcome to successfully implement that cell therapy. These difficulties include the definition of the most appropriated route for cell delivery and the number of cells to be injected, the improvement of MSC homing to damaged kidneys, the comprehension of MSC-host cells interaction, and the adverse effects of MSC engraftment (in vivo mal-differentiation and tumor formation).
MSC delivery route is a crucial aspect of cell therapy. As reviewed elsewhere, arterial route for progenitor/stem cell delivery promotes kidney regeneration more efficiently than intravenous route [
Stromal-derived factor (SDF-1) or CXCL12 binds to two receptors, CXCR4 and CXCR7. SDF-1/CXCR4 plays an important role in MSCs [
An emerging approach of MSC-based therapies includes the understanding of exosomes role in tissue regeneration. Exosomes are naturally occurring secreted membrane vesicles (30–40 to 100–120 nm) with a ubiquitous presence in biological fluids and an intrinsic homing ability. These extracellular vesicles are considered as important mediators of cell-to-cell communication, mediating the effects of MSCs on target cells, such as transfer of receptors, proteins, and genetic information (mRNA and microRNAs), as well as possessing a direct stimulation on target cells [
On top of that, a key aspect that can adversely affect the therapeutic potential of MSCs is the inflammatory environment at the site of the injury, since it can impact the survival and the engraftment of these cells. Furthermore, anti-inflammatory M2 macrophage-associated cytokines (IL-10, TGF-
Although there is evidence that MSCs can differentiate in vitro into mesangial cells when a coculture system of MSCs and oxidant-injured mesangial cells is established [
Taking a step forward, since companion or domesticated animals naturally develop many diseases that resemble human conditions, they represent, therefore, a novel source of preclinical models. Several diseases have been reported mainly in dogs, but also in cats, and include the chronic kidney disease (CKD) model. The majority of these studies, although uncontrolled, reported that MSCs are potential candidates for regenerating the damaged tissue, as reviewed by Hoffman and Dow [
Furthermore, feline chronic kidney disease (CKD) represents an ideal model to study the impact of drugs and cell therapy to reduce tubule-interstitial fibrosis and glomerulosclerosis, since CKD develops in 80–90% of these animals by age of 15 years. However, ADMSCs (adipose-derived MSCs) injection into cats via intravenous route, 2–4 × 106 cells, repeated three times, was not associated with improvement in renal functional parameters [
The number of registered clinical trials worldwide and MSC-based product Investigational New Drug (IND) submissions to Food and Drug Administration (FDA) have been increasing recently, as well as the diversity in donor and tissue source [
Several types of stem cells have been tested in a wide range of diseases and injuries, mainly in phase I/II trials: human embryonic stem cell-derived retinal pigmented epithelial cells for macular degeneration; human neural stem cells for stroke/cervical spinal cord injury; endothelial stem/progenitor cells for pulmonary arterial hypertension; and placental stem cells for stroke/rheumatoid arthritis/peripheral artery disease, for example, [
There is considerable heterogeneity in MSC protocols and a variety of sources used to isolate and manufacture the MSC populations for clinical trials [
A key aspect of MSC-based therapy is the isolation of MSCs from diabetic individuals for autologous transplant. It is reported that ADMSC from diabetic donors exhibits higher levels of cellular senescence and apoptosis when compared to nondiabetic ADMSC, as well as reduced capacity of osteogenic and chondrogenic differentiation [
Moreover, further characterization of MSC-based manufactured products to better understand the existence, phenotype, and MSC subpopulations is crucial for advancing MSC-based therapies.
In addition, some obstacles need to be overcome in order to provide safety for MSC-based therapies, such as cytogenic aberrations in mice-derived MSC (C57BL/6 and BALB/c) after several passages in vitro [
Although there have been major advances in the understanding of the molecular mechanisms that contribute to the development of DN, current best practice still leaves a significant treatment gap. Next, we discuss some perspectives, combined with current available treatment and/or MSC-based approach, that can ultimately contribute to halting the progression of DN, as summarized in Figure
Current treatment to prevent DN, MSC-based therapeutic approaches, and perspectives to halt the progression of DN.
No currently available treatments can prevent the development of diabetic nephropathy. The established therapeutic strategies are mainly based on strict control of glucose levels and blood pressure and blockade of the RAAS. These strategies may slow the progression of renal damage, but many patients still have progressive disease [
A new approach to the management of type 2 DM involves the reduction of renal glucose reabsorption through inhibition of the high-capacity and low-affinity sodium glucose cotransporter (SGLT2), found in the brush border of the first segment of the proximal convoluted tubules [
Mechanistically, SGLT2 inhibitors (empagliflozin, dapagliflozin, and canagliflozin) reduce proximal tubular sodium reabsorption, thereby increasing distal sodium delivery to the macula densa, which has been shown to activate tubuloglomerular feedback, leading to afferent vasoconstriction and a decrease in the hyperfiltration and intraglomerular pressure [
The randomized controlled trial EMPA-REG Outcomes with a 3.1-year follow-up documented that empagliflozin leads to significantly lower rates of death from cardiovascular causes (38%), hospitalization for heart failure (35%), and death from any cause (32%) [
Regarding renal outcomes in the EMPA-REG trial, empagliflozin was associated significantly with lower rates of incident or worsening nephropathy (12.7% versus 18.8%) [
In humans, the only adverse effect was genital and urinary infection in the empagliflozin group [
In
In the
Glucagon-like peptides 1 (GLP-1) receptor agonists and DPP-4 (dipeptidyl peptidase-4) inhibitors (incretin-based therapies) are also currently available strategies to prevent DN. One of these drugs, liraglutide, can ameliorate kidney fibrosis in a STZ-induced DN model in ED-1 mice by inhibiting TGF-
Podocytes exhibit high levels of constitutive autophagy, a pathway that delivers damaged proteins and organelles to lysosomes, representing a key protective mechanism against podocyte aging and glomerular injury [
Tight balance of mTOR activity is crucial for podocyte homeostasis. mTORC1-Raptor regulates autophagy, whereas mTORC2-Rictor is important for cell survival, metabolism, proliferation, and cytoskeleton maintenance. Genetic deletion of mTORC1 podocyte leads to proteinuria and progressive glomerulosclerosis in mice [
Conversely, mTORC1 is highly activated in podocytes of diabetic mice and patients and may be involved in the mechanisms of diabetes-related autophagy inhibition, which ultimately leads to early glomerular hypertrophy and hyperfiltration in diabetic nephropathy (DN) setting [
The intestinal microbiota is a complex ecosystem that affects human metabolism and may contribute to the development of obesity, insulin resistance, and subsequent type 2 diabetes. The ability of the intestinal microbiota to affect host metabolism is mediated by at least four components: dietary/nutrients intake, bile acids dehydroxylation, short chain fatty acid (SCFA) metabolism, and gut microbiota composition [
Of importance, metagenomic sequencing studies in Chinese and European individuals with type 2 DM indicate that functional alterations of their gut microbiome, for example, dysbiosis, might be directly associated with type 2 DM development [
Therapeutic interventions that manipulate the microbiota such as prebiotics, probiotics (live microorganisms), and fecal microbiota transplantation (FMT; infusing intestinal microbiota from lean donor) may have benefits in improving glucose metabolism and insulin resistance in the host [
However, it is yet to be proved whether intestinal microbiota plays a causal role in the pathogenesis of obesity and insulin resistance, as well as whether MSC-based therapy can modulate intestinal microbiota towards a less inflammatory environment in DN setting.
Nanoparticles possess numerous medical applications and are emerging as a class of carriers for drug and gene delivery.
As previously reported, cell-based strategy utilizing MSCs therapy is very promising for tissue regeneration [
The metallic nanoparticles is one of the most utilized, especially due the versatility of this platform, absent immunogenicity, and the ability to allow the cell tracking in vivo by single or multimodal imaging modalities [
However, understanding the nephrotoxic effect of the nanoparticles is a key aspect to successfully combine that technology with MSC-based therapy. Cytotoxic effects of metallic nanoparticles evaluated in human renal cell lines (IP15, glomerular mesangial cells and HK2, epithelial proximal cells) were mediated by oxidative stress and were associated with metal composition, particle scale, and metal solubility [
Nanoparticle diameter is also a crucial aspect for targeting kidney tissue. Therefore, gold-based nanoparticles of ~75 ± 25 nm may target the mesangium of the kidneys [
These new insights utilizing MSC therapy combined with nanoparticles are appealing and open new possibilities for the treatment of injured renal cells in DN setting.
Although exogenous MSCs exhibit therapeutic potential, endogenous MSCs do not migrate to damaged kidneys [
In human adult kidney, a hierarchical CD24+CD133+ population of progenitors cells organized in a precise sequence along Bowman’s capsule (PECs, parietal epithelial cells) was identified as a reservoir of cells that may contribute to the turnover of senesced or injured podocytes by proliferating, migrating, and differentiating from the urinary to the vascular stalk [
The leptin-deficient
In addition, since paracrine factors have been proposed as a key mechanism of benefit of MSC cell therapy, some studies pointed out that MSC may stimulate endogenous progenitor/stem cell proliferation and differentiation and therefore contribute to tissue repair [
Understanding why MSCs have the potential to stimulate endogenous progenitor/stem cells may enable the future development of pharmacoregenerative therapies, as well as improving current cell therapy strategies. If MSCs possess the capacity to stimulate kidney-derived progenitor/stem cells [
Induced pluripotent stem cells (iPSCs) are generated from somatic cells and represent a potentially inexhaustible cell resource with a pluripotent potential similar to embryonic stem cells. Functional MSCs derived from iPSCs possess similar mesenchymal characteristics of the naïve BM-MSCs, such as positivity for typical mesenchymal markers and negativity for endothelial and hematopoietic markers, as well as trilineage differentiation properties [
MSCs have several advantages for therapeutic purposes, such as their ability to migrate to injured tissues, strong immunosuppressive effects, safety profile, and lack of ethical issues, such as those related to the application of human embryonic stem cells. Therefore, MSC-based therapy is expected to become a promising strategy to slow DN progression because of their robust paracrine effects. Moreover, MSCs-based therapy combined with new drugs and/or novel therapeutic approaches, such as the modulation of fecal microbiota and renal autophagy, and the design of nanoparticles to enhance MSC effects will provide insightful strategies to prevent DN. In addition, the better understanding of the crosstalk between MSC and resident progenitor/stem cells may unveil a new mechanism of MSC therapy.
Despite the similarities between the sources of MSCs have already been documented, some important differences should be taken into account when choosing the MSC source for research or therapeutic purposes. Whether allogeneic and autologous MSC-based therapies harbor the same potential to treat kidney fibrosis in DN, there will be many MSC products that will meet the criteria for registered products in the established regulatory systems over the next years
To note, whether those findings in animals models will translate into reduced proteinuria and glycemia in humans with DN can only be determined in adequately powered, randomized, and controlled trials.
Adipose-derived MSCs
Advanced glycosylation end products
Animal Models of Diabetic Complications Consortium
Bone marrow-derived MSCs
Black and tan, obese, and tufted ob/ob (leptin deficient) mice
Chronic kidney disease
Dendritic cells
Diabetes mellitus
Diabetic nephropathy
Dipeptidyl peptidase-4 inhibitors
Endothelial nitric oxide synthase
Fecal microbiota transplantation
Glomerular basement membrane
Hepatocyte growth factor
Interleukin
Investigational New Drug
Interferon-
Lipopolysaccharide
Major Complex of Histocompatibility
Monocyte chemoattractant protein-1
Mesenchymal stem cells
Natural killer cells
Nonobese diabetic mouse
Parietal epithelial cells
Protein kinase C
Renin-angiotensin-aldosterone system
Short chain fatty acid
Sodium-glucose co-transporters
Streptozotocin
Transforming growth factor-
Tumor necrosis factor-
Urinary albumin excretion
Umbilical cord blood-derived MSCs
Ultrasound-targeted microbubble destruction
Vascular endothelial growth factor A.
The authors declare that they have no conflict of interests.
This work was supported by grants from FAPESP (