Mesenchymal stem cells and extracellular vesicles as therapy against kidney diseases
- Our review summarizes the mechanisms of action by which extracellular vesicles derived from mesenchymal stem cells (MSC-EV’s) treat common kidney diseases like acute kidney injury (AKI), chronic kidney disease (CKD), diabetic nephropathy (DN), and atherosclerotic renovascular disease (ARVD) in animal models. The research paper also mentions challenges from the current literature of research.
- Current common therapies are drug therapy (limited efficacy), dialysis (issues of inconvenience), and kidney transplantation (shortage of donors).
- Mesenchymal stem cells (MSC’s) are a new way to treat kidney diseases. MSC-EVs (MSC derived extracellular vesicles) seem more promising as it has several advantages including lower immunogenicity and tumorigenicity.
Biological characteristics of MSC’s
- There are two types of stem cells: adult stem cells (undifferentiated cells in mature tissues) & embryonic stem cells. MSC’s are a type of adult stem cell.
- Some sources of MSC’s are bone marrow, adipose tissue, human umbilical cord, human placenta, dental pulp, skin, blood, and urine. Existing literature mostly utilize bone marrow-derived MSC’s (BMMSCs), adipose-derived MSC’s (ADMSCs), and human placenta-derived MSCs (huMSCs).
- The main problem with MSC’s as a therapy is the lack of target specificity (Witte et al. and Schrepfer et al.).
- Some ways MSC’s are currently being administered are through systemic delivery (intra-arterial and intra-venous injection) and local delivery (topical, intra-muscular, direct tissue injection, and catheter-based direct implantation).
- Mechanism of action of MSC‘s include:
- Secreting trophic factors (growth factors, chemokines, cytokines).
- Delivering subcellular structures and mitochondria by forming tunnelling nanotubes with target.
- Secreting EV’s.
- Fusing with target cells.
Biological characteristics of EV’s
- Extracellular vesicles (EV’s) are a type of vesicle that are nanosized. Some types of EV’s are exosomes (Exos) – “containing DNA, RNA, proteins, and lipids”, microvesicles (MV’s), and apoptotic bodies.
- EV’s are mainly involved in intercellular communication.
- Their use as a non-invasive diagnostic marker has recently attracted major attention. Example: Exos are a marker for progression of AKI; EV’s also act as a marker in rejection of allogeneic heart transplantation.
- MSC-EVs specifically can delay progression of kidney disease due to their anti-apoptosis (anti cell death), anti-inflammation, anti-fibrosis, and antioxidation effects. They have also been found to improve renal function.
- EV’s can also be used as a drug carrier used to unload therapeutic compound / drugs at specific target sites. They have been used to carry antineoplastic and anti-inflammatory drugs.
- However, low retention and poor stability of EV’s post-translation have been limiting further clinical use. To address this issue, MSC-EV’s have been encapsulated in various compounds like collagen matrix, arginine-glycine-aspartate (RGD) hydrogel. This prolongs their retention and also induces sustained release.
- Moreover, based on the compound used for encapsulation, the therapeutic effect of EV’s are enhanced by means of pathological damage reduction, promotion of cell proliferation, and inhibition of renal cell apoptosis.
MSC-EV’s and AKI
- Initially, MSC transplantation had shown promise in treatment of AKI. Indeed the research progressed in such a manner that evidence pointed to the major role of MSC-EV’s in treating AKI.
- MSC-EV’s relieve AKI by inhibiting oxidation, apoptosis, and inflammation. They also regulate angiogenesis, cell cycle, regeneration, autophagy, and proliferation.
Some animal based AKI models:
I/R-induced kidney injury:
- The model is established by blocking the unilateral or bilateral renal arteries and veins in animals (rats are used mostly).
- Using huMSC-EV’s can alleviate the deficiency of blood in kidneys produced by obstruction of blood vessels.
- MSC-EV’s can inhibit macrophages which helps with immune suppression to reduce inflammation, apoptosis (cell death), this relieves AKI.
- EV’s derived from Human Wharton’s Jelly MSCs (hWJMSC-EV’s) decrease apoptosis (cell death) of the renal epithelial cells in kidney. They also have antioxidative effects which alleviate I/R induced kidney injury.
- MSC-Exo slowed progression of IRI (Ischaemia Reperfusion Injury) by inhibiting expression of inflammatory factors and apoptosis-related factors.
- BMMSC-EV’s modulate the function of mitochondria to play an antioxidative role.
Cisplatin-induced AKI model:
- This is a drug induced AKI model.
- BMMSC-MV’s protected the kidneys by helping with production of anti-apoptotic genes while inhibiting pro-apoptotic gene. They also alleviate cisplatin-induced cell injury.
- huMSC-Exo’s stimulate the proliferation of nephrocytes (group of cells present mostly in insects that filters toxins and waste from hemolymph – functions like the kidney in humans). They also can prevent cisplatin-induced renal toxicity.
- ADMSC-MVs’ regulate injured cells.
AKI model due to myolysis induced by glycerinum:
- In this model glycerinum is used to cause muscle disintegration (myolysis) and cause AKI.
- BMMSC-EV’s (mainly Exos) promote proliferation of tissue which helps relieve AKI. With some modification in structure of BMMSC-EV’s, they have also been used to simulate pro-regenerative effect and alleviate AKI induced by glycerinum.
- This model simulates sepsis-related AKI of critically ill patients.
- huMSC-Exos and ADMSC-Exo inhibit sepsis-related AKI in mice.
MSC-EV’s and CKD
- New evidence has shown that AKI may evolve to CKD.
- In a clinical trial of 7 eligible CKD patients involving an 18-month follow-up, single-dose autologous MSC’s have been proven safe and tolerable.
- huMSC’s relieve fibrosis via anti apoptotic and proliferating action.
- In mice models, MSC-EV’s, and EV’s have shown to improve the prognosis of kidney disease.
- BMMSC-Exos have been shown to alleviate renal interstitial fibrosis. huMSC-Exos also do the same. (Both in mice models).
- ADMSC-Exos facilitate regeneration of renal tubules in kidney thus slowing the AKI-CKD transition.
MSC-EVs and DN
- There are several investigations pointing to MSC transplantation’s effect in slowing progression of DN.
- A randomized controlled trial reported that it is safe to use mesenchymal precursor cells in type 2 diabetic patients. However, there can be immune rejection problems in allogenic transplantation. To address this issue, Nagaishi et al. used Wharton’s jelly to improve proliferation capacity and cellular mobilization capacity of diabetes derived BMMSC’s. This procedure has enabled effective autologous transplantation.
- MSC-EV’s are able to protect podocytes (cells in kidney) and other renal cells in kidney due to their anti-apoptosis, anti-fibrosis, and pro-autophagic effects. Pathological changes of podocytes are closely related to progression of DN.
- Exosomes derived from human urine-derive stem cells inhibit apoptosis of podocytes.
- ADMSC-EV suppresses apoptosis of podocytes in mice.
- MSC-MV’s restart cell cycle and reverse fibrosis in kidney cells.
- MSC-Exos enhance autophagy (mechanism by which cell removes damaged cells to regenerate newer cells) which has shown to delay DN.
- ADMSC-Exo also promotes autophagy and inhibits apoptosis in podocytes thus alleviating symptoms of DN.
MSC-EVs and ARVD (Conclusions cannot be drawn yet)
- ARVD can induce chronic renal ischaemia (reduced blood flow) and further lead to fibrosis. A common treatment for ARVD is surgery but, surgery doesn’t necessarily restore functions of dead tissues.
- Animal experiments have shown that MSC’s help restore functions of the kidney. In fact, several clinical trials have shown that infusion of autologous ADMSC’s in ARVD is safe.
- ADMSC-EV’s have improved renal function in pigs with renal vascular disease. They have also shown to relieve renal artery stenosis. (narrowing of renal artery)
- MSC-EV’s also have been shown to improve function of kidney with renal artery stenosis in animal models.
- ADMSC’s can better preserve microcirculation while ADMSC-EVs better retain intactness of nephrocytes and reduce necrosis (tissue death)
- Nevertheless, some research has shown that MSC-Exos only partially relieve ageing kidney induced renal artery stenosis. Thus, the value of MSC-EV’s in treatment of ARVD remains in dispute and further research is needed to reveal their efficacy.
MSC-EV’s and kidney transplantation (Conclusions cannot be drawn yet)
- Transplantation is the preferred treatment for end-stage renal failure patients. Unfortunately, there is a shortage of donors and transplants don’t last forever.
- In vitro studies have shown that adding MSCs/EV’s can protect the kidney from ischemic injury. They can also regulate immune reaction to allogenic kidney transplant to some extent.
- In a rat model of renal rejection, autologous MSC’s and not EV’s were shown to prolong the survival time of transplants and subjects.
- A trial with 105 kidney transplantation subjects who received autologous MSC’s suggested that it is safe to use in kidney transplantations. Moreover, another trial showed no significant protective and therapeutic effect of MSC’s in a 1-year follow up study. Hence, the protective effect of MSC-EV’s in a transplanted kidney is up for dispute and further research is needed before conclusions can be drawn.
- While there is much evidence in potential use of MSC’s in the treatment of kidney disease, there is still lack of research into the clinical use of MSC-EV’s. It might be that separation, purification, and mass production of EV’s still remains a challenge. Besides, there is a lack of understanding of exact mechanisms by which MSC-EV’s help treat kidney diseases.
- MSC-EV’s show promise as therapeutic agents in animal studies and some pre-clinical trials but further clinical studies looking into dosage, optimal source, route of administration, etc. are needed.
Watch this space for more developments in therapeutics.
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