Amniotic and chorionic membranes
During pregnancy, fetuses and amniotic fluid are involved by a fetal membrane responsible not only to protect them but also for allowing the exchange of nutrients and metabolic products with the maternal body. The amniotic membrane (AM) is the innermost part of the fetal membrane that directly contacts the embryo and aids its normal development by preventing the mother’s immune rejection and microbial contaminations. AM is a thin, translucent tissue composed of a single epithelial layer, a thick basement membrane, and an avascular stroma that retains exceptional mechanical and biochemical properties with proven clinical value. In the first years of its use, fresh human AM was clinically applied as a graft or biological dressing for the treatment of dermatological and ophthalmologic defects, such as wounds, burns, and non-healing ulcers. Since then, the introduction of improved processing and preservation techniques has expanded the applicability of AM-based biomaterials to more complex conditions, including organ and tissue regeneration (e.g. oral cavity, bladder, bone, and ocular surface). Currently, commercial products from human AM (e.g. AmnioGraftR and MiMedxR ) are already routinely marketed as effective tools for the treatment of conjunctival disorders (e.g. restrictive strabismus) and regeneration of damaged tissues (e.g. wounds) owing to this tissue’ innate ability to enhance wound healing, reduce scarring and inflammation, and prevent microbial infections.
Although the therapeutic behavior of AM is still not fully understood, the accumulation of anti-inflammatory cytokines (interleukin (IL)-10 and IL-1 receptor antagonist), antimicrobial peptides (β-defensins, elafin), and tissue inhibitor of metalloproteinases (TIMP-1, 2, 3 and 4) on the tissue extracellular matrix (ECM) and their slow release after implantation is a well-accepted explanation. Moreover, several other paracrine factors are thought to be involved by suppressing pro-inflammatory cytokines (IL-6 and IL-8), immune cells (T cells, B cells,, and dendritic cells), and chemotactic activities of macrophages and neutrophils that are typically recruited during the the host’s immune and inflammatory responses,, For example, the heavy chain–hyaluronic acid/pentraxin 3 (HC-HA/PTX3) complex, recently isolated from cryopreserved AM, was considered critical to this anti-inflammatory, anti-scarring and anti-angiogenic actions by inducing apoptosis of activated neutrophils and macrophages, enhancing phagocytosis of apoptotic neutrophils by macrophages, and reducing macrophage infiltration, while promoting their polarization towards M2 phenotype. Additionally, galectin-1, a glycan-binding protein found on various placental tissues including AM, has been mentioned to play a key role in the feto-maternal immune tolerance, thus suggesting its participation on the immunoregulatory and regenerative functions of these tissues.
Hematopoietic stem cells (HSCs)
Hematopoietic stem cells (HSCs) are the cells involved in hematopoiesis, the process by which all mature blood cells are produced. This means that HSCs have the capacity to differentiate into all blood cell types, including white blood cells, red blood cells, and platelets. Moreover, HSCs are multipotent and have the ability for self-renewal which makess them an attractive source of cells for TERM . In the human body,, they are primarily found in the bone marrow (BM) and rarely on the peripheral blood. Additionally, they can also be found on blood from newborn’s UC and placenta. Thus, the collection and banking of HSCs have become a popular option for use in cell therapies. In previous years, BM was considered the main source of HSCs for clinical application. However, the intricate harvesting of BM from donors has hampered the routinely and prompt utilization of this source. To overcome this limitation, clinicians started to use peripheral blood enriched with BM-derived HSCs that have been induced to migrate from BM to the bloodstream by the injection of mobilizing cytokines, such as granulocyte-colony stimulating factor. Soon after, UC blood emerged as a more straightforward and readily available source of HSCs which require neither the invasive harvesting nor the additional cytokine treatments. For this reason, UC blood has been extensively used in cellular therapies to treat disorders affecting the hematopoietic system, such as leukemia and Wiskott-Aldrich syndrome, and to help regrow healthy blood cells after chemotherapy.
Mesenchymal stromal cells (MSCs)
MSCs are multipotent progenitor cells that can differentiate into multiple cell types while maintaining their self-renewal capacity. In addition, MSCs possess immunosuppressive and antimicrobial properties that result from the release of bioactive factors, such as TGFβ-1, prostaglandin E2, nitric oxide, IL-6, and β-defenses, which make them attractive candidates for the treatment of conditions involving autoimmune and inflammatory components (e.g. graft-versus-host disease). Although BM-MSCs iscurrently the “gold standard” source of MSCs for pre-clinical and clinical applications, some limitations related to painful harvestings, low isolation yields, donor-related variabilities, and limited in vitro expansion and differentiation efficiency, have motivated the search for alternative sources either in adult (adipose, muscle, and connective tissue) or perinatal tissues (amniotic fluid, placenta, fetal membranes, and UC).
Extra-embryonic cell sources are particularly interesting as cells can be readily harvested in large numbers using non-invasive strategies and without fostering typical ethical concerns (since it is a material usually discarded). To date, several cell populations have been identified on perinatal tissues that display multilineage differentiating ability and are capable of self-renewal. This includes cells from the maternal origins, such as decidua-derived MSCs (D-MSCs), but especially from fetal origin including those from the chorionic villi (CV-MSCs), amnion (AM-MSCs), chorion (CM-MSCs) amniotic fluid (AF-MSCs), and umbilical cord (UC-MSCs), particularly from Wharton’s jelly (WJ-MSCs).
Conclusions and future perspectives
TERM has evolved as a promising interdisciplinary field that combines cells, scaffolds, and biomolecules. Although great advances have been done regarding the design of biocompatible scaffolds and their conjugation with stem cells, some issues continue to hamper the clinical translation of these therapies. The use of animal sources to prepare scaffolds and grafts, for example, continues to raise ethical and safety concerns due to the frequency of immunogenic rejection and the risk of xenogeneic diseases transmission; on the other hand, the use of cadaveric and fetal human tissues is usually associated with serious ethical and/or legal concerns which highly limit their use. Alternatively, human perinatal tissues have recently started to be explored as a valuable source of materials and stem cells for TERM. It is clear from the works herein reviewed that the range of applications for perinatal tissues-derived materials and cells has been rapidly growing. So far, researchers proved that these materials are capable of improving healing and promote regeneration mainly due to their anti-inflammatory, anti-fibrotic, immunomodulatory and anti-bacterial properties. Although these features are intrinsically associated to the ECM of perinatal tissues, it is now well established that resident stem cell populations also play a pivotal role on the bioactivity of these biomaterials. Therefore, not only perinatal tissues but also their derivate cells have been isolated and used to develop innovative therapies.
Author: Inês A. Deus, João F. Mano, Catarina A. Custódio