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| REVIEW ARTICLE |
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| Year : 2015 | Volume
: 1
| Issue : 2 | Page : 119-124 |
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Amniotic fluid-derived stem cells as an effective cell source for transplantation therapy in stroke
Nicholas S Diaco, Zachary M Diamandis, Cesar V Borlongan
Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa, Florida, USA
| Date of Submission | 03-Aug-2015 |
| Date of Acceptance | 21-Nov-2015 |
| Date of Web Publication | 31-Dec-2015 |
Correspondence Address:
Cesar V Borlongan
Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, 12901 Bruce B. Downs Boulevard, Tampa - 33612, Florida
USA
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/2394-8108.172881
This review examines stem cells harvested from human amniotic fluid and considers their possible applications in regenerative medicine, specifically for stroke therapy. Providing an early-stage, highly differentiable source of mesenchymal stem cells, amniotic fluid shows the potential to be effective in the development of future stem cell-based transplantation. This paper underscores the importance of pursuing amniotic fluid as a stem cell source in stroke therapy, citing both the characteristics and the demonstrated functional benefits of these cells in animal models. Additional research is required to discover the full range of amniotic fluid-derived stem cells' (AFSCs) applications but these cells have thus far demonstrated the ability to be applied to a wide array of existing and future treatment methods. Both amniotic fluid- and amnion membrane-derived stem cells (AMSCs) have their merits, and this assessment will accordingly provide a comparison of the benefits and drawbacks of both cell sources. Keywords: Placenta, regenerative medicine, stem cells, tissue engineering, transplantation
How to cite this article:
Diaco NS, Diamandis ZM, Borlongan CV. Amniotic fluid-derived stem cells as an effective cell source for transplantation therapy in stroke. Brain Circ 2015;1:119-24 |
| Introduction | |  |
Studies exploring both the human amnion and amniotic fluid as stem cell reserves for regenerative medicine have been increasingly prevalent in the recent literature. An examination of the differentiation potential of the cells from these two sources has revealed their high degree of plasticity. [1] Several lines of investigations have focused on amnion membrane-derived stem cells (AMSCs), highlighting their ability to promote reepithelialization, modulate differentiation and angiogenesis, and decrease inflammation, apoptosis, and fibrosis. [1],[2],[3],[4] In this paper, we seek to deviate from this trend and explore the lesser examined amniotic fluid-derived stem cells (AFSCs), revealing their potential applications in stroke therapy.
| Stemness of Cells Derived From The Amniotic Fluid | | |
The cells harvested from amniotic fluid are characterized as stem cells due to their specific pluripotency markers and gene expression. Molecular analysis of the human second-trimester AFSCs revealed the presence of several genes associated with early germ cell development, namely, Fragilis, Stella, Vasa, c-Kit, and Rnf17. [5] Furthermore, this analysis showed the expression of pluripotency markers such as OCT4 and SOX2. After their aggregation to form embryoid bodies (EBs), AFSCs demonstrate the ability to reacquire many commonly lost characteristics of early stage embryogenesis. [5] More specifically, the cells from these AFSC-derived EBs are seen to express alternate spliced exons characteristic of pluripotent stem cells, such as the exon 10 of DNMT3B and the b isoform of Sall4. In addition, these cells are shown to express markers of the three embryonic germ layers such as GATA4, GATA6, AFP, and Nestin. Finally, these cells appear to lack X chromosome inactivation. [5] The important role of AFSCs in embryogenesis is further suggested by this last observation, as there may be a correlation between genomic reprogramming events and the reactivation of the inactive X chromosome. Induced pluripotent stem cells (iPSCs) can be easily obtained from reprogramming the readily abundant CD117-negative populations of human amniotic fluid mesenchymal stromal cells (hereafter denoted as AFMSCs) by using nonintegrating Sendai viral vectors encoding OCT4, SOX2, KLF4, and cMYC. [6] It is important to note that these iPSCs are viable generators of sufficiently homogenous populations of neural progenitors and are virtually identical to human embryonic stem cells in several assays, adding to their already promising engraftment potential in vivo. [6] Moreover, these neural progenitors are capable of differentiating into astrocytes and mature neurons in vitro. [6]
Furthermore, the gene expression profiles of AFMSCs are mostly characteristic of undifferentiated cells. [7] As shown through reverse transcription polymerase chain reaction (RT-PCR) analysis, [7] AFMSCs consistently express genes for Rex-1, SCF, GATA-4, vimentin, CK18, HLA ABC, and FGF-5 during the culture period in addition to expressing genes for BMP-4, nestin, AFP, and HNF-4α. This vast array of genes is responsible for regulating many different cell types, suggesting that AFMSCs have the potential to express various pluripotent stem cell-specific genes and to proliferate considerably during ex vivo expansion. The genes expressed also indicate their capacity to differentiate into a multitude of cell types such as adipocytes, osteocytes, chondrocytes, and neuronal cells. [7]
Even though AFSCs' capability of in vitro differentiation into cell lineages from all three germ layers shows great promise, much work remains to be done. One area of chief importance is the further assessment of AFSCs' immune properties. Hugely beneficial to future applications is AFMSCs' low immunogenicity; studies have observed AFMSCs expressing several immunosuppressive factors such as HLA-G and CD59 (protectin), resulting in a notable resistance to rejection. [8] Unlike the HLA-A and HLA-B genes, HLA-G is expressed in the placenta, playing an essential role in immune tolerance during pregnancy. [8] CD59 impedes the complement attack complex and prevents the complement system from damaging cells by binding C5b678 and inhibiting C9 from binding and polymerizing. [8] Other recent studies have made apparent AFMSCs' immunomodulatory properties, which render the cells capable of inhibiting T lymphocyte proliferation. [8] In another study, late-passage AFSC cultures displayed an increase in the population of CD105+ cells compared to that of early-passage cultures. [9] Two reasons that AFSCs have been suggested to represent cells of mesenchymal precursor lineage include the fact that CD105 is an established mesenchymal marker and that long-term culture conditions can give rise to mesenchymal cell growth. According to recent in vitro analysis, lymphocyte proliferation is regulated by AFSCs in different ways according to the gestational age (i.e., AFSCs obtained from the first, second, or third trimester). [10] The most efficient inhibition of T and natural killer cell proliferation was seen with first-trimester AFSCs, whereas second- and third-trimester AFSCs were less effective in this respect. [10] Furthermore, B cell proliferation could only be suppressed by inflammatory-primed second-trimester AFSCs. [10]
As documented in the previous studies, the properties of AFSCs vary from donor to donor in addition to maintaining common characteristics of both embryonic and adult stem cells. [11] Furthermore, the differentiation capacity of AFMSC preparations is not influenced by the protein expression of cells initially found in AFMSCs (PMID: 25608581). An alternate technique of inducing pluripotency could be provided by the ectopic expression of Oct-4 in hAFMSCs, [12] whereas SOX9's selective expression and Wnt signaling induction may be used in conjunction to differentiate cells to neurons and promote neurogenesis, respectively. [13],[14] Nonetheless, before any of these methods can be put into practice, an appropriate cryopreservation protocol such as the slow-freezing solution must be identified and tested. [15] In one study, a feeder layer derived from inner stem cells was used in order to direct AFSCs to differentiate into neurons with characteristics of functionality. [16] This study also revealed an important connection between the triggering of neurogenesis and the Wnt signaling pathway. [16] Taking these many practical qualities into consideration, it is clear that AFSCs will serve a very important role in cell transplantation strategies for stroke therapy.
| Transplantation Studies Using Amniotic Fluid Stem Cells for Stroke Therapy | | |
Accounting for about one in every 19 deaths, stroke is the fourth leading cause of death among adults in the United States as of 2010. [17] Intravenous recombinant tissue plasminogen activator, a thrombolytic, is currently the only nationally approved treatment for acute ischemic stroke. Unfortunately, this treatment must be administered within a short 3-h window after symptom onset in order to be effective. Thrombolytic therapy administered after stroke has resulted in a significant reduction in the number of deaths and individuals requiring assistance with daily activities. [18] However, the risk of death within the first 7-10 days, the occurrence of intracranial hemorrhaging, and the likelihood of death at a 3-6 month follow-up are all amplified by this treatment. [18] The intravenous delivery of bone marrow- and perinatal-derived cells may serve as a possible first week therapeutic intervention during the restorative phase. [19] These cells are able to translocate to areas of tissue injury and target brain remodeling. [19] Stroke is a time-sensitive acute injury; the brain may respond better to this model of transplantation in comparison to other organs or system diseases characterized by ongoing degenerative processes or immunological attacks. [20]
An ectodermal cell lineage serves as the source for developing neurons. Previous research has shown the ability of AFSCs to differentiate along a neurogenic pathway. [21],[22] Transplantation of AFSC-derived cells has been explored in the treatment of several neurological disorders such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), spinal cord injury, and several others [7],[23],[24],[25],[26] but there is markedly less work focused on using these cells as a source for transplantation in stroke. The concept of poststroke AFSC transplantation is driven by the objectives of contributing to functional improvement and promoting restorative mechanisms such as neurogenesis, angiogenesis, and immunomodulation. [20]
A novel study on mice examined the utilization of AFSCs for focal cerebral ischemia-reperfusion injury and its resulting behavioral effects. [27] In this study, injury was induced by 60 min of middle cerebral artery occlusion followed by a 7-day reperfusion phase. Intracerebroventricular delivery of AFSCs resulted in a noticeable reduction in neurological sequelae and behavioral deficits. Furthermore, the study indicated that embryonic neuronal stem cells, which typically carry ethical concerns, are comparable in terms of benefits when compared to the less controversial AFSCs. [27] It should also be noted that the intravenous delivery of AFSCs, which is significantly less invasive than intracerebroventricular delivery, offers a similar level of efficacy in regenerative injury treatment. [25] Although the blood-brain barrier may limit the effectiveness of cells delivered intravenously in some cases, the potential of this transplantation method should nonetheless be further explored.
Preclinical data have shown that ideal transplantable stem cell candidates for future clinical trials in stroke should display attenuate brain inflammation accompanied by behavioral improvement after transplantation. [28] Interestingly, AFSC transplantation has demonstrated such functional effects in experimental stroke models, and parallel clinical studies have also demonstrated a considerable improvement in patients' cardiac function, possibly indicating that these cells are cardioprotective. This may allow clinical trials to be extended to individuals with stroke of cardiovascular etiology. [29] The phase of the stroke, i.e., acute or chronic, will likely be a major determinant of the administration route of AFSC transplantation. As mentioned previously, an effective model of cryopreservation for these cells will be necessary in order to assure that AFSCs are readily available for administration in any given phase of stroke. [28]
Using rats, our laboratory has examined the use of amniotic fluid stem cells to treat cerebral ischemia-reperfusion injury after stroke. [30] Behavioral tests were used to examine neurological abilities before middle cerebral artery (MCA) occlusion, after MCA occlusion, and after transplantation of amniotic fluid-derived cells at day 35. These tests included the rotarod test and the elevated body swing test. The data from these examinations indicated that AFSC transplantation lessens infarct volume and neuron loss, diminishes deficiencies in memory and learning, and promotes cell proliferation. [30]
Thrombolytic therapy reduces the harmful effects of stroke but is limited by a short treatment window and health risks. Stroke treatment utilizing intravenous delivery of bone marrow- and perinatal-derived cells may be more effective and have fewer negative side effects. AFSCs, with their ability to differentiate along a neurogenic pathway, have already been investigated in the treatment of a number of neurological disorders but their use in stroke therapy has not yet been sufficiently examined. Several studies, including one from our laboratory, have shown that AFSC transplantation shows both behavioral and physiological improvement in animal stroke models. Much work remains to be done before these methods can be put into practice but the possibility of clinical application exists.
In addition to treating acute ischemic stroke, stem cell therapy may be helpful for long-term recovery in hemorrhagic stroke patients. Hemorrhagic strokes constitute less than 20% of all strokes but are difficult to treat and have a high mortality rate; researching their treatment is of utmost importance. [31] Recent studies have tested stem cell therapy for treatment of hemorrhagic stroke. [31],[32] In one study, groups with intracerebral hemorrhage or ICH showed a statistically significant improvement with limb-placing and rotarod tests after receiving stem cells. [31] A second study showed that adipose-derived cell treatments after ICH promoted functional recovery in modified limb-placing tests. [32] However, neither of these papers have examined hemorrhagic stroke treatment using AFMSCs. Further research may reveal that the amniotic fluid can provide a source of cells effective in not only treating ischemic stroke but also hemorrhagic stroke.
| Advantages and Disadvantages of Amniotic Fluid Versus Amnion Membrane Stem Cells | | |
In contemplating amnion fluid and amnion membrane use in cell therapy, it is important to consider both the advantages and disadvantages of AFSCs and AMSCs. A summary of these inspections is offered in [Table 1]. First, stem cells from the amniotic fluid can be sourced much earlier than cells from the amniotic membrane; in particular, amniotic fluid can be collected during amniocentesis after a few months of pregnancy, whereas the amnion membrane is only accessible after childbirth. This difference is of paramount importance to the cells' utility; the early collection time of AFSCs allows individuals to isolate, culture, and amplify the population of cells prior to birth so that any disease developed during or soon after delivery (i.e., hypoxia) may be attended to immediately with the child's own stem cells. AMSCs harvested from the amnion membrane, on the other hand, may require several weeks to be serviceable. By the time that the number of AMSCs is sufficient for transplantation, the narrow therapeutic window may have already passed. The collection of AFSCs in an earlier developmental stage may additionally increase the differentiation potential of the cells, suggesting a greater range of therapeutic applications. Second, the earlier harvesting period of AFSCs drastically improves the feasibility of autologous transplantation in comparison to stem cells taken from the amniotic membrane. While AFSC treatment harnesses the benefits of using a donor's own cells, AMSC transplantation is generally performed as an allogeneic procedure due to the time required to accrue a sufficient amount of stem cells. Third, the safety of both the stem cell-collecting procedures must be taken into account. The requirement of amniocentesis in order to access AFSCs may cause unnecessary injury to the mother and/or the child. In contrast, postbirth AMSC collection poses no risk to the health of the mother and child. Thus, harvesting stem cells from the amnion membrane is considerably safer than amniotic fluid collection. Amniotic fluid may alternatively be recovered after childbirth but this limits the previously stated benefits of earlier collection. Fourth, amniotic fluid contains many fewer stem cells when compared to the amnion membrane. Although this makes the culturing and amplification of AMSCs markedly easier, the earlier collection time of AFSCs allows plenty of time for amplification. Finally, the lineage of stem cells derived from the amniotic fluid is more difficult to isolate and confirm, as these cells require phenotypical characterization to obtain homogenous populations. Despite this, AFSCs have been proven to differentiate into multiple lineages. [5],[33],[34],[35] Conversely, the origin of cells making up the amnion membrane is well-understood. Most AMSCs can be shown to be of epithelial and mesenchymal origins, allowing ease of isolation and further differentiation. [36] However, recent studies have demonstrated that the trophic factors secreted by stem cells, as opposed to regeneration or differentiation, are responsible for most of their therapeutic effects. [25],[37] These studies may eliminate the need for homogenous cell populations as long as therapeutic outcomes are achieved. | Table 1: Advantages and disadvantages of amniotic fl uid-derived stem cells and amnion membrane-derived stem cells
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| Tissue Engineering and Regenerative Potential of Amniotic Fluid Stem Cells | | |
AFSCs and AFMSCs have prospective applications in the fields of tissue engineering and regenerative medicine for stroke, as they possess useful therapeutic properties. Studies concerning traumatic brain injury (TBI) have suggested that AFSCs/AFMSCs assist in the formation of subdural patch-like networks known as biobridges. Analysis of notch-induced human bone marrow-derived mesenchymal stromal cells during regeneration in a rat TBI model demonstrated the grafted cells' ability to harness biobridge formation. [38] These biobridges act as a biological conveyor belt, moving both transplanted exogenous stem cells and the host's own endogenous stem cells to the site of injury across nonneurogenic tissue. [38] Along this line of investigation, harmful inflammation inherent in TBI that may inhibit cell differentiation can be suppressed by combining AFMSCs' potential to differentiate into neural progenitor cells with this novel bone marrow-derived mesenchymal stromal cells' biobridge-based tissue engineering. Despite the absence of a detectable immune response in graft-host integration after biobridge formation, the use of an amniotic fluid subdural patch as an adjunct to bone marrow-derived mesenchymal stromal cell transplantation can further block any graft-host immunologic reaction, thereby serving as either a standalone or an adjunct therapeutic agent for regenerative medicine.
Many health disorders, specifically neurological diseases, may be treatable with allografts. Allograft tolerance can be defined as the lack of a negative reaction by the host's immune system in response to the alloantigens of a transplant. The first phase of immune response, the innate and nonspecific response, is activated early in allograft rejection. T lymphocyte recognition of the alloantigens marks the beginning of the subsequent phase: The donor-specific adaptive immune response. [39] AFMSCs' immunomodulatory properties have the potential to reduce chronic immunosuppression and encourage long-term allograft acceptance. [8],[40]
AFMSCs not only reduce the immune and inflammatory response elicited by allografts but may also amplify the therapeutic outcome of xenograft transplantation. However, the transfer of cells and organs between two distinct species often has immunological repercussions. The host frequently rejects the xenograft due to xenoreactive antibodies, which activate the complement system and cause systemic inflammation. [41],[42] Cell survival rates have shown no improvement even with immune tolerance methods such as neonatal desensitization. [43] In previous studies, however, xenograft acceptance has been facilitated through the use of anti-CD4/CD8 therapy in combination with circulating anti-inflammatory alpha-1-antitrypsin (AAT). [44] In this regard, the co-transplantation of immunosuppressive amniotic fluid stem cells introduces the possibility of AFMSCs as new tactic to combat xenograft rejection.
The potent combination of trophic factors produced by AFMSCs is known to enhance angiogenesis in addition to stimulating both the mitosis and differentiation of a host's own reparative and stem cells, especially in stroke models. [37],[45] One study analyzing the effects of neurotrophic factors produced by AFMSCs following sciatic nerve crush injury in rats showed significant improvement in nerve regeneration, motor function recovery, nerve conduction latency, and the compound muscle action potential, further demonstrating the therapeutic potential of AFMSCs' secreted trophic factors. [46] It has also been suggested that donor cells may undergo gene therapy to enhance the secretion of specific growth factors directed to promote the level of angiogeneic, vasculogenic, or neurogenic factors in the stroke brain. [25]
AFSC therapy is still in its infancy but its vast potential may provide the basis for future cell-based stroke therapeutics. In particular, AFSCs may be intravenously transplanted in tandem with other noninvasively administrated drugs to create a novel combination therapy that is wholly safe and atraumatic for the patient. Several compounds such as melatonin and various growth factors have already been considered, [47],[48],[49] and experimental drugs are also being developed for this purpose. In most cases, studies have shown that the coupling of these different therapies elicits a number of synergistic effects that result in a highly effective treatment with benefits that neither treatment displays independently. Several existing classes of standalone drugs such as racetams and racetam derivatives have also been demonstrated to show a noticeable improvement in stroke patients [50],[51] but may harbor even greater effects when used together with stem cell therapy.
| Conclusion | | |
Despite the fact that stem cells derived from the amniotic membrane have been more closely investigated than those from amniotic fluid, AFSCs show great promise for future clinical applications. AFSCs are an ideal cell source, providing easy access either during or after pregnancy, simple isolation and amplification of stem cells, the ability to differentiate into many different cell types, the potential to exercise immunomodulatory effects, and a lack of major ethical concerns. By promoting neurogenesis, angiogenesis, and immunomodulation, AFSC transplantation may very well provide us with a new and effective treatment option for ischemic stroke patients. Although many practical characteristics have already been observed, the full range of AFSCs' applications and its optimal administration procedure will have to be determined through future research. Further investigation of these cells' great potential may provide an unprecedented development in the fields of regenerative medicine and tissue engineering for the treatment of stroke and other neurological diseases. Vis-à-vis comparisons between AFSCs and AMSCs as well as with other stem cell types may prove beneficial in identifying optimal transplantation regimens that are safe and effective for stroke and other specific neurological disorders.
Financial support and sponsorship
Nil
Conflicts of interest
There are no conflicts of interest.
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[Table 1]
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