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Pediatric Nephrology

, Volume 33, Issue 6, pp 935–945 | Cite as

Amniotic fluid cells: current progress and emerging challenges in renal regeneration

  • Stefano Da Sacco
  • Laura Perin
  • Sargis Sedrakyan
Review

Abstract

Amniotic fluid (AF) contains a heterogeneous population of cells that have been identified to possess pluripotent and progenitor-like characteristics. These cells have been applied in various regenerative medicine applications ranging from in vitro cell differentiation to tissue engineering to cellular therapies for different organs including the heart, the liver, the lung, and the kidneys. In this review, we examine the different methodologies used for the derivation of amniotic fluid stem cells and renal progenitors, and their application in renal repair and regeneration. Moreover, we discuss the recent achievements and newly emerging challenges in our understanding of their biology, their immunoregulatory characteristics, and their paracrine-mediated therapeutic potential for the treatment of acute and chronic kidney diseases.

Keywords

Amniotic fluid stem cells Renotropic factors Kidney disease Stem cell therapy Renoprotection 

Introduction

The kidney has some capacity to repair after mild injury [1], but when damage involves a significant portion of the renal tissue or is recurrent, the intrinsic regenerative mechanisms alone are insufficient to halt progression of kidney disease. When this capacity to self-repair is exhausted, progression turns into an irreversible process, leading to kidney failure. Cellular therapies have been shown to provide some therapeutic benefit in the kidney, with the potential to slow down disease progression. In particular, cell therapies with bone marrow-derived hematopoietic stem cells (BMSCs) [2, 3], mesenchymal stem cells (MSCs) [4, 5], adipose-derived stem cells (ADSCs) [6, 7], endothelial progenitor cells [8, 9, 10], and amniotic fluid (AF)-derived stem cells [11, 12, 13] have been successfully exploited in preclinical models of acute and chronic kidney injury. Cells from AF can be easily collected by amniocentesis, expanded, and characterized in culture [14]. The isolated cells present a heterogeneous population, including mesenchymal cells, organ-specific progenitor cells, and mature cells. Pluripotent stem cells and organ progenitors from AF have been successfully differentiated into adult tissue types and have been further tested for their potential to treat diseases of different organs, such as the lung, the pancreas, the kidney, and others. This review highlights the regenerative and therapeutic role of AF cells, with a special focus on the current knowledge of their characteristics, capacity for renal differentiation, and their potential to treat acute and chronic kidney diseases.

Amniotic fluid: molecular and cellular composition

Amniotic fluid is a clear liquid that fills the amniotic cavity surrounding the developing fetus. Its main function is to provide a protective environment during all stages of fetal development. It also helps to regulate the temperature of the fetus during pregnancy. The volume and composition of AF change during pregnancy following the physiological variations of the developing fetus. During embryogenesis, maternal plasma is the main contributor to AF volume increase thanks to the osmotic flow of water through fetal membranes, and later on, through the placental membrane [14, 15]. During the first few weeks of gestation, AF composition is comparable with that of fetal plasma and it is only after the 8th week of gestation that the fetal kidney begins fluid production, and rapidly increases in volume during the second trimester. The exchange of fluids through the skin is present until keratinization between 20 and 24 weeks of gestation [15]. AF cell composition is heterogeneous, consisting of cells derived from all three germ layers that persist until around 17–18 weeks of gestation [14, 16, 17]. Mesenchymal and hematopoietic progenitor cells have also been shown to exist before the 12th week of gestation in humans [18], together with cells expressing neuronal, cardiac, and pancreatic phenotypes [14, 19, 20, 21]. Notably, the presence of pluripotent cells (evaluated by expression of pluripotent markers such as octamer-binding transcription factor [OCT] 4 and cluster of differentiation [CD] 117) remains stable during the entire stretch of gestation [14, 22], possibly suggesting that the AF microenvironment promotes the maintenance of pluripotent characteristics in specific subsets of cells [23].

Isolation, expansion, and characterization of pluripotent cells

Successful isolation of pluripotent cells from AF is possible from a variety of sources, including humans [20, 24, 25], rodents [26, 27], equine [28, 29], ovine [30, 31], bovine [32, 33], caprine [34], canine [35, 36], and porcine [37]. Currently, several methodologies are practiced for the isolation of AF stem cells, such as:
  1. 1.

    Adherent cells, isolated without the use of specific antibodies (unselected cells)

     
  2. 2.

    Adherent cells isolated through CD117 immuno-selection (CD117-positive cells)

     
  3. 3.

    Isolation of colony-forming cells

     
In addition to various isolation strategies, media and culture vessels used for their expansion widely vary among groups, thus possibly contributing to the derivation of different populations of AF stem cells. For the purpose of this review, we refer to amniotic fluid stem cells (AFSCs) when discussing cells isolated through CD117 selection, amniotic fluid mesenchymal stem cells (AF-MSCs) when describing unselected cells, and amniotic fluid colony forming cells (AF-CFCs) when discussing cells obtained using colony-forming techniques.

Isolation of pluripotent cells of human and mouse origin based on CD117 expression was first reported by De Coppi et al. in 2007 [38], and characterized by the expression of surface markers and transcription factors distinctive from embryonic stem cells (ESCs) such as OCT-4 and ​stage-specific embryonic antigen 4 (SSEA-4). AFSCs are positive for a number of surface markers characteristic of mesenchymal and pluripotent cells, including CD29, CD44 (hyaluronan receptor), CD73, CD90, and CD105, whereas they lack the expression of hematopoietic markers CD34 and CD45 [38].

Kunisaki et al. established one of the first methodologies for the isolation of AF-MSCs from human samples at between 20 and 37 weeks of gestation [22]. Unlike AFSCs, AF-MSCs are isolated using an in vitro cell cultivation method where no initial positive (for any specific stem cell marker) or negative selection is performed. To this end, various protocols have been established for the isolation and expansion of AF-MSCs, including the use of different growing surfaces, culture media or derivation of clonal cell lines.

The AF-MSCs and AF-CSCs share similar marker expression with AFSCs. For example, Wang et al. confirmed that almost all AF-MSCs were positive for CD44, CD90, and CD147, partially positive for CD29, CD105, and CD106, and negative for CD34 and CD133 [39], whereas Phermthai et al. showed that AF-CSC express OCT4, SSEA4, CD29, CD44, CD73, CD90, CD105, and CD133 [40]. Collectively, regardless of their method of isolation and presentation of few variations in some markers, these stem cell populations have very similar surface expression profiles, whereas some markers are recurrent (CD44, CD90, CD29). They have also been applied in various applications for kidney regeneration with equivalent success.

Plasticity of AF cells toward a renal fate

Pluripotent cells derived from AF can differentiate into a wide range of functional cell types, including but not limited to neuronal progenitor cells [41, 42, 43], cardiac muscle cells [44, 45], endothelial cells [46, 47], pancreatic cells [48, 49], liver cells [50], lung precursor cells [51], and dermal sweat gland cells [52]. However, few studies have investigated their potential toward a renal fate. To better recapitulate the specific niche of the developing renal compartment, differentiation of AFSCs and AF-MSCs was tracked within developing fetal kidneys. For example, we have previously shown that AFSCs can integrate into the embryonic murine kidney and contribute to the development of primordial nephrogenic structures, such as renal vesicle and C- and S-shaped bodies, while also expressing early renal markers such as zonula occludens 1 (ZO-1), glial cell-derived neurotrophic factor (GDNF), and claudin [53]. In 2009, Siegel et al. showed that following supplementation of the culture media with fibroblast growth factor 4 (FGF4)/hepatocyte growth factor (HGF) and epidermal growth factor (EGF)/platelet-derived growth factor (PDGF), AFSCs could undergo mesenchymal-to-epithelial transition, maintaining expression of mesenchymal markers CD29 and CD44 while acquiring expression of epithelial markers CD51 and ZO-1 and podocyte markers such as CD2-associated protein (CD2AP) and podocin. However, the functionality of the cells was not tested [54]. In a further look at the renal potential of AFSCs, Siegel et al. in 2010 followed the formation of chimeric renal structures ex vivo by mixing dissociated murine embryonic renal cells with human AFSCs. Human cells integrated into the developing murine tissue, expressed paired box 2 (PAX2; ureteric bud and nephron structures), E-cadherin (epithelial marker), Wilms tumor 1 (WT1; differentiating nephrons and, in the adult, restricted to podocytes), and calbindin (marker of the branching ureteric bud). Interestingly, they also linked the ability of AFSCs to differentiate into renal cells with the activation of the mechanistic target of rapamycin (mTOR) pathway. Inhibition of the pathway significantly decreased commitment of AFSCs toward a kidney fate [55]. More recently, AFSCs genetically modified to express GDNF were shown to differentiate toward a functional podocyte-like cell expressing several podocyte markers, including nestin, podocin, α-actinin-4, and organized foot processes with intact interposed slit diaphragms. In a model of chimeric aggregates of dissociated murine embryonic kidneys and AFSCs implanted under the kidney capsule of uninephrectomized athymic rats, GDNF-expressing AFSCs appeared functional and showed the internalization of exogenously infused bovine serum albumin [56]. In another recent work, expression of renal markers SIX2, CD24, and kidney-specific protein (KSP) was confirmed in an AF-CFC population, suggesting the existence within AF of kidney-specific cells with pluripotent/multipotent traits in the late (third trimester) stages of gestation [57].

Amniotic fluid progenitor cells

The presence of cells within AF committed to different cellular fates represents a unique advantage of the AF cell population. In particular, as AF and fetal kidney are in contact during development, it is plausible to hypothesize that some cells might escape the developing kidney, possibly during the transition from the pronephron to the metanephron, and reside within the AF. Indeed, we reported the isolation of a progenitor population with renal traits [58]. These cells, characterized by the co-expression of CD24, OB-cadherin and podocalyxin (namely amniotic kidney progenitor cells [AKPCs]) confirmed their ability to differentiate into mature and functional podocytes, expressing slit diaphragm markers, producing and assembling the collagen IVα3α4α5 trimer, and exhibiting functional responses to nephrotoxic and therapeutic agents. Moreover, we reported that these progenitors also express SIX2 and CITED1 [58], markers of the uninduced metanephric mesenchyme [59]. The ability of these AKPCs to differentiate into renal cell types in vivo and their therapeutic effect in animal models have not yet been investigated.

Application of AF pluripotent cells to kidney therapy

Despite the increasing prevalence of end-stage renal failure and its associated morbidity and mortality worldwide, therapies aimed at treating kidney diseases have lacked significant progress in the last decades, thus increasing the need to develop alternative strategies. In this regard, AF-derived cells have emerged to possess potential not only as a model to study renal differentiation, but also as a tool to understand disease progression. In particular, application of these cells using in vivo animal models of acute and chronic kidney injury has been instrumental in our understanding of their therapeutic potential. With an in vitro potential to differentiate into a vast array of cell types, it has been important to determine if AF-derived stem cells could potentially act as precursor cells when injected in vivo to replace damaged renal cells after injury. Despite the expectation, however, studies using various injury models demonstrating cellular engraftment and differentiation have not prevailed because only a small fraction of cells remained in the target organ, whereas most of the therapeutically injected cells (regardless of their route of administration) end up in other organs (such as the spleen and lungs) or would be eliminated. Importantly, the lack of significant engraftment and differentiation of AFSCs in the kidney was still accompanied by positive therapeutic outcomes that were subsequently attributed to their immunomodulatory potential. The following sections summarize these observations in further detail and focus on elucidating the ability of AFSCs to migrate to the site of injury, exert immunomodulatory activity, and promote tissue preservation.

Preclinical models of acute kidney injury

Rhabdomyolysis and cisplatin-induced acute tubular necrosis

Initial attempts to determine the therapeutic effect of AFSCs (of human origin) in an experimental model of acute kidney injury (AKI) were reported by our group [60]. Using a glycerol-induced rhabdomyolysis model of acute tubular necrosis (ATN) in nu/nu mice, we showed that the intra-renal injection of AFSCs during the acute phase of ATN did not rescue kidney damage, as demonstrated by increased serum creatinine and blood urea nitrogen (BUN) levels. However, simultaneous injection of both glycerol and AFSCs ameliorated kidney injury resulting in the absence of creatinine or BUN peak. Moreover, tubular epithelial cells were protected from damage, demonstrating reduced cast formation, less apoptosis and greater proliferation. AFSCs appeared to also modulate the inflammatory response, as demonstrated by the inhibition of pro-inflammatory cytokines and increased expression of anti-inflammatory interleukins, such as IL-10 and IL1RA. Moreover, although few AFSCs were found to express aquaporin-1 (proximal tubular marker) and GDNF (nephrogenic marker) within tubular and glomerular compartments respectively, their commitment toward a renal fate does not appear to be the main mechanism of their reno-protective activity. Using the same rhabdomyolysis-induced ATN model of AKI in severe combined immunodeficiency (SCID) BALB/c mice, Hauser et al. showed that AF-MSCs, when injected intravenously 72 h post-glycerol injection, still accelerated tubular recovery by enhancing proliferation and reducing tubular endothelial cell apoptosis [61]. The extent of protection provided by AF-MSCs in this study was comparable with that obtained from injection of BMSCs, with the exception that AF-MSCs lodged much longer within the renal parenchyma and seemed to have a more prolonged anti-apoptotic effect than BMSCs. In contrast to our study, however, AF-MSCs and BMSCs in the latter case did not integrate into kidney structures, but rather remained localized in the renal interstitium [61]. It is important to note that these two studies differ in terms of their cell derivation methods, the route of administration and the timing of injections; yet, they provided comparable protection in both cases, reporting functional improvement and suggesting a paracrine mechanism of renoprotection through the secretion of soluble mediators.

Several studies have also assessed the regenerative potential of AF-MSCs in cisplatin-induced acute nephrotoxicity models in rats and demonstrated that a single injection of cells could accelerate the recovery of kidney damage, significantly improve renal function, and reduce oxidative stress, thus enhancing the regenerative capacity of the kidney [62, 63]. AF-MSCs seem to have outperformed BMSCs and adipose-derived stem cells (ADSCs) in their regenerative capacity, providing greater proliferative power to the kidney [63]. Furthermore, AFSCs enhanced by GDNF preconditioning were shown to exert added protection from cisplatin-induced nephrotoxicity in immunodeficient non-obese diabetic(NOD)/SCID mice [12]. As reported, pretreatment of AFSCs with GDNF improved renal function and tubular cell proliferation significantly, beyond the capacity of the unstimulated cells alone, possibly by activating stem cell cytoprotective and antioxidant pathways. In addition to GDNF, other local paracrine factors may potentially be involved in mediating the regenerative effect of AFSCs, including IL-6, vascular endothelial growth factor (VEGF), stromal cell-derived factor 1 (SDF-1), and insulin-like growth factor 1 (IGF-1) [12].

Ischemia and reperfusion injury

Unfortunately, renal ischemia and reperfusion (I/R) is an inevitable occurrence in the kidney transplantation process [64]. It is an important cause of acute renal failure in allografts and native kidneys equally [65]. Several studies have shown the beneficial effect of AF stem cells in the context of I/R injury. Clonal AF-MSCs positive for CD24, KSP, SIX2, and PAX2 expression demonstrate strong protection against ischemic injury in 12-week-old male Wistar rats, as shown by Monteiro Carvalho Mori da Cunha et al. [57]. Intravenous injection of AF-MSCs 6 h post-I/R injury are beneficial as early as 24 h after treatment, as demonstrated by decreased serum creatinine level and presentation of less severe morphology in the form of hyaline cast formation and tubular necrosis. AF-MSC treatment also resulted in higher proliferation of tubular epithelial cells accompanied by decreased macrophage infiltration and myofibroblast activation. In the long term, AF-MSCs seemed to have an inhibitory effect on the progression of chronic kidney disease, as demonstrated by a relatively lower level of microalbuminuria and fibrotic index in treated animals 2 months after injury [57]. Secretion of soluble factors by exogenous stem cells is a mechanism of renoprotection seen in various models of kidney injury. As this hypothesis currently dominates our understanding of stem cell bioactivity, there have been attempts to enhance this therapeutic potential by the modulation of one or more of these trophic factors [66, 67, 68, 69, 70]. A recent study demonstrated that moderate VEGF upregulation in AF-MSCs enhances protection from I/R injury by reducing inflammatory response [66]. Similarly, reports of umbilical cord-derived MSC enhanced for IGF-1 [67] and HGF [68] expression have shown increased protection against gentamicin and I/R-induced AKI respectively. Other attempts with the overexpression of BMP-7 in BMSCs have also been reported to enhance renal repair [69], whereas TGFβ promoted the homing of the MSCs [70] in renal I/R injury. Taken together, these observations provide important insights into the regulatory pathways that play an essential role during tissue remodeling. A slight alteration in signaling such as VEGF [71], TGFβ/BMP7 [72], and angiotensin II [73] could significantly alter the homeostasis of kidney function by changing the morphology and behavior of the target cells, triggering inflammatory and fibrotic responses that if persistent, ultimately progress to renal failure. It has been shown for example that administration of a single dose of AF-MSCs (1 × 106 cells) overexpressing VEGF stimulated a greater inflammatory response and augmented I/R injury compared with two consecutive half-dose injections (5 × 105 cells per injection, [66]). These data thus suggest that signaling networks operating under normal conditions providing baseline communication between cells in the kidney, such as the cross talk that occurs across the glomerular basement membrane between podocytes and glomerular endothelial cells, might be tightly regulated. Therefore, efforts aimed at establishing the therapeutic range for many of these trophic factors by means of cellular approaches would be an important step toward finding well-balanced and effective cellular and molecular strategies to promote pro-healing reparative and regenerative processes in the kidney.

Preclinical models of chronic kidney disease

Despite the growing interest in AF-derived stem cell approaches as an alternative to reversing or slowing down kidney disease, very little is known about the therapeutic potential of AF stem cells in the setting of chronic kidney disease (CKD). In recent years, only a handful of studies investigating the therapeutic effect of AF cells in advanced fibrotic kidney diseases have been described. We reported for the first time that a single systemic injection of clonal AFSCs into mice with Alport syndrome before the onset of proteinuria significantly slows down disease progression, demonstrated by alleviated glomerular and interstitial fibrosis, improved kidney function and prolonged survival in mice [11]. Injected cells that lodged within glomerular capillaries prevented podocyte loss, the culprit in most glomerulopathies. Our study suggests that AFSCs could mediate such effects by secreting paracrine signaling factors locally within the glomeruli, promoting anti-inflammatory conditions by mediating macrophage M2 polarization and potentially through angiotensin II blockade [11]. In addition, Sun et al. reported that transplantation of AF-MSCs into nu/nu mice with unilateral ureteral obstruction alleviated the progression of renal fibrosis by increasing VEGF-mediated angiogenesis and decreasing HIF-1α and TGF-β1 expression [74]. Moreover, AF-MSCs improved proximal tubular cell density by promoting their proliferation and decreasing apoptosis. Taken together, these studies indicate that AF stem cells do not seem to integrate in the kidney during CKD, but rather act as transient regulators of the injury processes, promoting the activation of regenerative mechanisms through the secretion of renotropic healing molecules.

Renotropic factors and kidney remodeling

Despite the growing importance of the stem cell-derived soluble mediators in kidney remodeling, very few publications have investigated their basal production secreted by AF pluripotent cells in vitro. Although not specifically focusing on renal regeneration, Yoon et al. characterized the AF-MSC secretome and confirmed the expression of EGF, a factor known to favor renal regeneration [75]. We recently evaluated the effect of decellularized renal extracellular matrix on AFSC differentiation and secretome profile, and found that the cell–matrix interaction stimulated the secretion of several cytokines, chemokines, and soluble factors known for their renotropic activity, such as PDGF-AA and PDGF-BB [76] and IL6 [77]. However, the mechanism by which these growth factors could facilitate recovery, and how stem cells can contribute to this process, remain elusive. Regardless of their source, period of gestation during derivation and method of selection, AF stem cells have clearly demonstrated their beneficial effect in various kidney injury models (Table 1). Given the fact that only a fraction of cells eventually reach the kidney after transplantation [11] and that they only stay in renal compartments for a relatively short time, their role in regulating the endogenous renal cells and tuning the local environment to promote healing seems to be an important component of their mechanism of action [11, 12, 13].
Table 1

Summary of recent literature and its major findings on amniotic fluid stem cell therapy for kidney disease

Animal species

Disease model

Cell type

Stem cell isolation method

Observations

Tropic factors

Reference

Wistar rat

Ischemia–reperfusion

hAF-MSC

Gestational week 19; monoclonal

Low-dose VEGF enhanced AFSC protect the kidney from I/R injury by increased vessel formation, decreased tubular necrosis, and fibrosis

VEGF

Mori da Cunha et al. [66]

Wistar rat

Ischemia–reperfusion

hAF-MSC

Gestational week 19; monoclonal

Cells detected in the kidney at 6 h after injection, but not at 24 h. Decreased inflammation and interstitial fibrosis; proteinuria ameliorated

iNOS, eNOS

Monteiro Carvalho Mori da Cunha et al. [57]

Pig

Auto-transplantation

Porcine AF-MSC

End of gestation; adherent cells

Improved kidney function, reduced tubular atrophy and prevented development of fibrosis

VEGF, TGF-β Ang1, Flt1

Baulier et al. [13]

Sprague–Dawley rat

Transplantation

rAF-MSC

Total amniotic fluid cells grown in suspension cultures, in bottles

Alleviated injury and oxidative stress level, mproved kidney function in the transplanted kidney via inhibition of CD4+ and CD8+ cells, in addition to IL-4 and IFN-γ

SeGSHPx antioxidant

Feng et al. [78]

Sprague–Dawley rat

Cisplatin-induced toxicity

hAF-MSC

Unselected adherent cells

Increased regenerative power compared with hADSC and rBMSC

Paracrine factors

Ashour et al. [63]

Sprague–Dawley rat

Cisplatin-induced toxicity

hAF-MSC

Unselected adherent cells

Accelerated the recovery of kidney damage, improved renal function, and reduced oxidative stress

n/a

Al-Husseiny et al. [62]

Mouse NOD/SCID

Cisplatin-induced toxicity

hAFSC

CD117 (c-kit) positive cells isolated by immunoselection

Improved survival in AKI mice likely through release of paracrine factors. GDNF preconditioning leads to improved outcomes

IL-6, VEGF, SDF-1, IGF-1

Rota et al. [12]

SCID BALB/c

Glycerol-induced ATN

hAF-MSC vs MSC

Unselected adherent cells

Histological and functional amelioration. AFSCs were more antiapoptotic to tubular cells than the MSC

LIF, VEGF

Hauser et al. [61]

nu/nu mouse

Glycerol-induced ATN

hAFSC

CD117 (c-kit) positive cells isolated by immunoselection. Monoclonal

Attenuation of the acute phase of disease. Morphological and functional improvement. Accelerated tubular proliferation, decreased cast formation, and apoptosis of TECs

IL-10, IL1RA, IL-6

Perin et al. [60]

nu/nu mouse

UUO

hAF-MSC

Unselected adherent cells

AFSCs contribute to angiogenesis, alleviate tissue hypoxia, increase TEC proliferation and prevent apoptosis resulting in improved kidney morphology. HIF1a and TGF-β are reduced

VEGF

Sun et al. [74]

Mouse

Alport syndrome (knock-in mutation)

mAFSC/clonal

CD117 (c-kit) positive cells isolated by immunoselection. Monoclonal

Reduced interstitial and glomerular fibrosis, improved kidney function and prolonged survival. Podocyte preservation observed

Angiotensin II pathway inhibition

Sedrakyan et al. [11]

h human, r rat, m mouse, NOD/SCID non-obese diabetic/severe combined immunodeficiency, ATN acute tubular necrosis, UUO unilateral ureteral obstruction, AF amniotic fluid, MSC mesenchymal stem cell, AFSC amniotic fluid stem cell, VEGF vascular endothelial growth factor, CD cluster of differentiation, IL interleukin, IFN interferon, ADSC adipose-derived stem cell, BMSC bone marrow mesenchymal stem cell, AKI acute kidney injury, GDNF glial cell-derived neurotrophic factor, TEC thymic epithelial cell, HIF1a hypoxia-inducible factor 1-alpha, TGF transforming growth factor, iNOS inducible nitric oxide synthase, eNOS endothelial nitric oxide synthase, SeGSHPx selenium glutathione peroxidase, n/a not available, SDF-1 stromal cell-derived factor 1, IGF-1 insulin-like growth factor 1 , LIF leukemia inhibitory factor, IL1RA interleukin-1 receptor antagonist

Immunological characteristics of AF cells and their potential application in regenerative medicine

Immunogenicity of AF cells

Translational application of exogenous stem cells brings with it the possibility of allogeneic immunogenicity that requires serious consideration and continues to challenge the advancement of the field. Over the years, the problems associated with potential immunogenicity in using human ESCs, for example, their ability to form teratomas, in combination with the widely propagated ethical concerns, have seriously hindered the clinical translation of ESCs [79, 80, 81]. Although the introduction of human induced pluripotent stem cells (iPSCs) has considerably eliminated these concerns, risks associated with reprogramming somatic cells, using either viral or nonviral plasmid-based approaches, remain. Some of these risks, including potential alteration in de-differentiation unrelated to other genes, including epigenetic changes due to lengthy in vitro culture manipulations that iPSCs must undergo before they are generated, are still a major roadblock to their therapeutic use [82]. Thus, AF stem cells present a viable alternative because of their high expansion potential in vitro, but more importantly, because of their ability to avoid strong immunogenic response and are also devoid of ethical considerations. More specifically, AFSCs are characterized to be positive for MHC class I (human leukocyte antigen [HLA]-A, -B, -C), but the expression of MHC class II (human leukocyte antigen-D-related [HLA-DR]) is not detectable. They are also negative for co-stimulatory molecules (CD80, CD86) [38, 83]. When activated in vitro with IFN-γ, AFSCs show increased expression of MHC class I and II, but not CD80 or CD86, suggesting an ability to avoid allogeneic rejection [83]. Both AFSCs and AF-MSCs were shown to inhibit lymphocyte activation and suppress inflammatory responses in vitro [83, 84]. AFSCs were shown not only to better inhibit T cell proliferation and Th1 polarization than MSCs, but they also promoted Th2 polarization with direct production of IL-10 and IL-4, and stimulated Th17 to increase production of anti-inflammatory cytokines IL-6 and IL-17 [84]. Importantly, these cells are able to secrete anti-inflammatory cytokines such as IL-10 and IL1-Ra, and reduce the induction of pro-inflammatory cytokines, such as TNFα. When co-cultured in vitro with peripheral blood mononuclear cells (PBMCs) activated with phytohemagglutinin (PHA), anti-CD3mAb or staphylococcal enterotoxin B (SEB), they were able to inhibit T-cell proliferation. Interestingly, the inhibitory behavior was triggered only in response to signals released by activated immune cells, such as T, B, and NK cells, which were not constituently present at the basal level [84]. Moreover, AFSCs obtained from an earlier gestational age display greater immunomodulatory capacity than cells derived later during gestation [85]. In particular, they possess stronger inhibition of T cell and NK cell proliferation, and lower expression of HLA class I molecule and NK-activated ligands than cells obtained in the second and third trimesters [85]. These features of AFSCs could potentially be advantageous in promoting immune tolerance after transplantation that could ultimately translate into improved therapeutic outcomes. As challenges in antibody-mediated rejection after renal transplantation remain unresolved, despite recent advances in immunosuppression, the potential of stem cells as an alternative means of solving this particular problem has attracted increasing attention in recent years [86, 87]. In renal transplantation studies on rats, AF-MSCs have been shown to induce immune tolerance, preventing the infiltration of inflammatory cells and oxidative stress levels by inhibiting the proliferation of CD4+ and CD8+ cells and secretion of inflammatory factors IL-4 and IFN-γ, similar to results obtained with MSCs inhibiting the acute rejection of a rat kidney graft [78]. The ability of AF stem cells to reduce toxicity and I/R-associated damage, enhancing graft survival in organ transplantation, is of significant clinical value.

Potential future clinical strategies

Studies in rodent models of acute and chronic kidney disease of varying etiology have provided substantial evidence demonstrating the therapeutic ability of AF stem cells to modulate disease course. Supporting evidence from larger preclinical models of kidney disease is also encouraging. AF-MSC administration in a porcine model of kidney transplantation, where injection of AF-MSCs into the renal artery 6 days after autotransplantation provided strong protection against fibrosis and improved kidney function [13]. Porcine AF-MSCs showed comparable expression of stemness markers such as CD90, CD29, and CD73, consistent with an MSC profile. Only CD105 expression was reported to be low, corresponding to the late time of gestation at which the cells were harvested, as also reported previously by our group [14]. Interestingly, porcine AF-MSCs in this particular study seem to provide a clinical benefit through modulation of pro-angiogenic pathways, as demonstrated by a significant increase in VEGF-A and angiotensin II, and an equivalent decrease in Flt1 expression in kidneys as late as 3 months after stem cell transplantation. Thus, the ability of AF stem cells to mediate activation of protective mechanisms in AKI seems to be relatively consistent across different studies, encompassing cells of diverse origin, ranging from human to mouse to pig. These studies collectively suggest that AF activates a broad spectrum of paracrine signaling networks responding to the stimuli released from stem cells in the form of trophic factors such as cytokines, growth factors, and might even involve transfer of genetic material such as microribonucleic acid (miRNA) through the release of extracellular vesicles or exosomes [88]. Among the multitude of factors released by exogenous stem cells, several of them, including IGF-1, HGF, VEGF, and EGF, seem to play key roles in mediating the renoprotective mechanisms observed in an AKI setting [66, 67, 68]. We believe that transplantation of AF stem cells represents a potential strategy for future clinical applications as a safe and effective means of treating renal disease. Given their unique immunogenic profile, AF stem cells could potentially allow for both autologous and allogeneic transplantations devoid of complications associated with immune rejection. Therefore, it is plausible to assume that AF stem cells could be collected, characterized, frozen, and banked to then serve as a universal source of stem cells that can benefit multiple patients. Similar to the umbilical cord blood banking strategies, there have been efforts in recent years to create banks of AF. This is indeed an important step that could potentiate a significant number of new clinical trials. Banks of AF stem cells could therefore be created following similar strategies. Given the vast heterogeneity in the HLA system with an ever-growing number of alleles, allogeneic rejection cannot be completely ruled out [89]. It is not realistic to consider developing a fully matched HLA source of stem cells, but reducing the number of haplotypes that would fit the requirement for a diverse population may be achievable. Therefore, the banking of AF stem cells may allow some of these challenges to be overcome by minimizing allogeneic differences between donor and recipient using improved HLA matching.

As the field continues to advance and our understanding of the cellular mechanisms that trigger protective behaviors, such as secretion of trophic molecules and cytokines, improves, opportunities for the development of potential new strategies to treat kidney diseases without the direct application of amniotic cells, as an alternative, may become a future possibility. Recently, for example, extracellular vesicles derived from stem cells have been identified to mediate effects similar to that created by the cells of their origin (Scheme 1) [88]. These extracellular vesicles can transfer their contents (proteins and RNAs) to other cells, regulating several biological processes, including immune response, metastasis, angiogenesis, and cellular survival [90]. Thus, elucidating the extracellular content of stem cells derived from AF could help to establish a safer and more efficient therapeutic use of AF cells for kidney therapy.
Scheme 1

Use of amniotic fluid-derived cells for renal regenerative medicine

Importantly, the in vitro ability of AF stem cells to acquire renal cell phenotypes through differentiation could have other potential implications for renal regenerative medicine, such as for tissue-engineering approaches to rebuilding the kidney. Interestingly, in recent years, efforts have been made to repopulate decellularized matrices with cells for the purpose of recreating functional kidney units [91, 92, 93]. Strategies of cell delivery through the renal artery and ureter have been used to deliver different cell types to their appropriate niche in the kidney parenchyma. Such experiments have been attempted using ESCs and human umbilical venous endothelial cells (HUVECs) delivered via the renal artery and rat neonatal kidney cells (NKCs) through the ureter [91, 92, 93, 94]. Transplantation experiments in rats with bioartificial scaffolds were reported to restore glucose and electrolyte reabsorption when seeded with HUVECs and NKCs [94]. In another study, rat scaffolds seeded with murine embryonic cells presented no observable signs of rejection for 2 weeks, after which the renal artery and vein had thrombi blocking sufficient blood flow [95]. Similarly, renal progenitors and stem cells derived from amniotic fluid could be used as source cells to repopulate decellularized scaffolds, as described earlier [76, 96].

Even though the integration and differentiation of AF stem cells after direct transplantation does not seem to be important in defining their therapeutic role in in vivo disease models, their plasticity could eventually be utilized in tissue-engineering applications of the kidney, as described.

Final remarks: advantages and challenges

Amniotic fluid harbors a heterogeneous population of cells that can be used for both in vitro and in vivo studies. In vitro differentiation of amniotic pluripotent and progenitor cells into kidney-like cells with little or no manipulation allows investigations involving renal cell specification and differentiation, in addition to the creation of ex vivo models of the renal compartment such as organoids or kidney-on-a-chip systems. These are emergent technologies that may recapitulate important embryological and pathological processes of the native kidney by recreating the biological niche outside of an organism. Development of such tools holds great promise for the study of cellular interactions, drug toxicity, disease modeling, and regeneration of the kidney after injury (Scheme 1). In contrast, in vivo applications of AF cells have been instrumental, not only for their evaluation as therapeutic tools, but also for exploring novel mechanism(s) of kidney remodeling that occur(s) after a significant insult.

Despite the abundance of encouraging data, several issues may hamper the initiation of clinical trials of these cells. In fact, the lack of a harmonized and clear nomenclature, the absence of standardized isolation, expansion protocols, and the use of cells derived from different species in various animals challenge the interpretation and comparison of experimental results.

Although it has been widely recognized that the main mechanism of reno-protection is primarily defined by paracrine activity rather than by integration and differentiation in vivo, our current understanding of the underlying mechanisms by which AF cells exert their effect on kidney calls for further investigation. At present, we are only beginning to understand some of the components of complex mechanism(s) that may be involved in and responsible for the observed outcomes, which include, but are not limited to, the secretion of growth factors, trophic molecules, cytokines, and extracellular vesicles.

Overcoming these challenges will eventually define the level of efficacy of AF-derived stem cells for clinical use. Meanwhile, their contribution as a research tool has been of great value and could have a significant impact on the advancement of the science of renal medicine.

Notes

Compliance with ethical standards

Conflicts of interest

The authors declare that they have no conflicts of interest.

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Copyright information

© IPNA 2017

Authors and Affiliations

  1. 1.GOFARR Laboratory for Organ Regenerative Research and Cell Therapeutics, Children’s Hospital Los Angeles, Division of Urology, Saban Research InstituteUniversity of Southern CaliforniaLos AngelesUSA

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