However, after i. The authors demonstrated that the mean size of the MSCs was larger than the size of the pulmonary capillaries. Thus, large amounts of injected MSCs could be trapped in lung capillaries, preventing access to other organs. Further, lung localization could be reduced by a vasodilator.
The findings related to MSC biodistribution seem to be limited by vasculature-related issues, such as vessel size and pressure, and by still unclear intrinsic MSC properties, such as cytoskeletal activity, migration capacity, or cell size, that affect specific organ localization. Engrafted GFP-positive cells were then harvested from bone and infused into secondary recipients.
Stem Cells: Basics and Clinical Translation
Curiously, after systemic delivery of these bone-derived MSCs, cells could only be detected in skeletal tissues and not in the lungs or liver, indicating that intrinsic MSC properties and physiological microenvironmental cues were able to select specific MSC sub-clones associated with a defined biodistribution pattern in the lack of pathological conditions. After xenotransplantation, MSCs underwent site-specific differentiation into chondrocytes and in cardiomyocytes, and, even after development of fetal immunocompetence, MSCs maintained their underlying ability to differentiate in several tissues and maintained their multipotentiality and immunological advantage.
Despite that fact, allogeneic MSCs exhibited longer survival than skin fibroblasts, but their survival was shorter than that observed in syngeneic or immune-deficient recipients. More recently, some authors have suggested that immunosuppression by MSC may also be exerted after cell destruction, opening the field to novel investigations aimed at a deeper understanding of how dying MSC could be immunosuppressive.
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Inflammatory signals may also affect MSC biodistribution. MSC i.
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Interestingly, MSC migration in the abdomen was more prominent after i. These data support i. In addition, pathological conditions and related factors i. Cancers have also been reported as pathological conditions capable of influencing MSC biodistribution. The distribution pattern of the migrated MSCs was similar in normal and tumor-bearing mice, although there was a significantly higher presence of labeled MSCs in the brains of the cancer group, with a brain tropism that appeared to be proportionally inverse to the lung localization.
The authors demonstrated migration of labeled cells near the lesion area until the third week after injection. Although the liver has been reported as the target organ under steady-state conditions, liver diseases may influence MSC distribution.
Perspectives for Clinical Translation of Adipose Stromal/Stem Cells
Considering the variability in biodistribution after intravascular delivery and accounting for the fact that local delivery could be appropriate for defined indications, several research groups focused their attention on local MSC transplantation. Interestingly, a signal could also be detected in the spleen, indicating that i. Robust investigations of these aspects are lacking, partly because of the difficulty of developing standardized approaches to their study.
Therefore, in this analysis, we sought to further dissect factors involved in the setup of an MSC preclinical biodistribution study. One of the key factors influencing PD is represented by the MoA and its related therapeutic effect. Indeed, if differentiation is the leading process in MoA, then the cells might be more effective when directly implanted in their site of action; conversely, if secretion is prevalent, then cells can be active even when administered remotely i.
Zhao, Robert Chunhua
A further issue relates to MSC therapeutic targets, which can be localized or widely scattered in the body and influence the selection of a local versus systemic route of administration. Other PD factors to be considered are represented by pathophysiological aspects involved in the often chaotic background of the target disease and its related microenvironment. These variables may influence the choice of MSC source, cell doublings, number of injected cells, and route of administration. Also, in this case, the detection and selection of the bioactive substances and efficacy biomarkers can be modified based on the need to treat an acute or chronic state rather than a young or old patient.
The pathologic microenvironment to which MSCs are exposed has also become progressively more relevant. The abundance of bystander cells as well as their recruitment and function represent potent PD-influencing factors. MSC-related PK factors are related to the cells themselves intrinsic factors , and non-MSC factors are related to the techniques introduced in a biodistribution study extrinsic factors. A biodistribution study is dependent on cell-related factors, including the size, the source, the cell doubling, and the immunogenicity of the cells.
This parameter, dependent on the age and passages in culture, 70 can be responsible for trapping in the lung after systemic administration. It is well known that bone marrow, adipose tissue, and fetal annexes are the most often used MSC sources because of similarities and despite some differences in morphology, the number of isolated cells, and the ability to differentiate in tissues.
For example, it is known that adipose tissue and umbilical cord MSCs give origin to adipogenic, 71 chondrogenic, 72 and osteogenic 73 lineages. MSC sources can also influence basic cellular features such as surface cellular markers and size. The injected MSCs should preferably be derived from young donors and undergo low culture passages to preserve the proliferation potential and prevent oxidative stress because increased donor age seems to be correlated with detrimental effects on proliferation and differentiation abilities.
Essentials of Mesenchymal Stem Cell Biology and Its Clinical Translation - Semantic Scholar
In addition to cell and donor age, culture conditions also influence cell performance and senescence, consequently affecting the number of cells administered. As described, two of the reasons for wide diffusion of MSC transplantations are the high degree of safety as well as the low risk of rejection. Nevertheless, porcine MSCs, one of the most used alternatives to human MSCs, can undergo genetic modifications that further decrease their hypoimmunogenic potential, allowing them to be fully protected from the host immune response.
Extrinsic cell-related factors focus on the variables dependent on the setting of a biodistribution study, such as labeling, route of administration, animal models, and detection methods. The cell labeling and the detection methods are relevant for suitable MSC tracking. Genetic labeling e. This gene labeling is preferred for long-term studies because detection can be maintained after mitosis, although it is potentially associated with genetic instability following transduction. On the contrary, chemical labeling has a shorter duration than genetic labeling because it is diluted in daughter cells after cell division.
The choice of animal size is dependent on the preclinical investigation phases. In early stages, it is preferable to use small animals, whereas large animals are often required in later stages to mimic the clinical setting; further, in this way, the route of administration must mimic the one intended for clinical trial. For example, therapeutic targeting can be prevented after systemic delivery because of the pulmonary first pass.
Because most of the studies were performed while considering—almost exclusively—PD aspects, we maintain that the PK aspects need attention. PK describe the time course of drug disposition after administration, and PD focuses on the observed effects resulting from delivery of a drug. In this range, no adverse events should occur, and the drug should be considered safe.
Consequently, monitoring of drug concentration is a key step when defining a drug regimen, related to both efficacy and safety. Therefore, defining the cell number responsible for the intended pharmacological effect represents a challenge. Like cells, small molecules may also undergo variability in their concentrations when they reach the systemic circulation. Although the PK of a chemical compound are typically dependent on well-characterized properties during drug development, such as the administration route, physical chemistry e.
Physiologically based PK modeling PBPK has been introduced during drug development, with the aim of predicting the drug disposition of a candidate compound using preclinical PK data. On the basis of known kinetics data from selected publications, the authors presented a two-compartment model that simplifies the biodistribution of MSCs after i. A Two-compartment pharmacokinetic model of mesenchymal stromal stem cells MSCs after intravenous i. R i , injection rate; R c , clearance rate; K 1 , rate of extravasation; K 2 , rate of intravasation. C Apparent engraftment of MSCs with a decaying retention of 24 h.
The apparent activity is considered to be the product of the unit activity per cell and the number of cells remaining after injection. The analysis is taken from Parekkadan and Milwid. However, based on experimental evidence of MSC i. The clearance rate R c and the rate of intravasation K 2 are higher than the rate of extravasation K 1. Consequently, the exchange between the 2 compartments is practically null, and the MSCs stay in the central compartment.
This may need to be addressed by comparative clinical trials in which cells are delivered daily versus weekly, as is currently done for GVHD treatment. Although i. Moreover, undefined mechanisms of action and the high connection of MSCs within the neighboring environment make these cells non-inert particles whose biological activity can be dependent on many bioactive circulating factors that are released directly or indirectly by injected MSCs or by other cells i. This aspect adds a complexity that needs to be addressed by new models, and the high variability of biomarkers detected needs to be considered in a novel PK-PD prediction.
Consequently, the final apparent activity will be the result of all of the different biomarkers acting within a defined time frame and also involving bystander cells. This model, defined as two functional compartments, is based on the fact that, after infusion, MSCs can release molecules cell-related biomarkers capable of functionally influencing bystander cells i. In addition, considering that microenvironment cues may influence MSC-related biomarker release, we should consider that the effect of MSCs on bystander cells could be temporally shifted, affecting the PD of infused cells.
MSC administration. The authors describe that MSCs can release prostaglandin-E2 PGE2 as a cell-related biomarker , which acts on PGE2 receptors of activated macrophages PGE2 and E4 receptors , which induces the release of interleukin IL; an efficacy biomarker , whose function is then to reduce inflammation by acting on immune cells. Much of the data supporting this concept have been reported.
A Mesenchymal stromal stem cells MSCs are challenged in a sepsis model after i. The PD biomarkers are the cytokines as markers of the therapeutic activity. This review focuses on MSC biodistribution, addressing the PK and PD aspects of these intriguing stromal progenitors, originally reported in the s. Despite the growing applications of MSCs in trials, much still needs to be addressed regarding their biodistribution, especially because clinical success of an MSC-based product should require preclinical research with appropriate PK-PD investigations in early phases of development to better understand MSC functions and increase their efficacy in patients.
In this way, the progression of MSC-based therapy toward improved clinical development could be expedited, and early interruptions or unexpected results in later phases could be avoided. Then decisions can be made regarding other PK factors that could differentially affect biodistribution. Indeed, if PD factors are mandatory to define both cell-related and efficacy biomarkers, then PK factors are dependent on those which affects the overall quality of the study.
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This approach may be particularly valuable for diseases like pulmonary disorders, including asthma, acute respiratory distress syndrome ARDS , chronic obstructive pulmonary disease COPD , and idiopathic pulmonary fibrosis IPF , , , which are ranked by the World Health Organization WHO as leading causes of death. Often the pathogeneses of lung disorders are not completely known, and the molecular target to trigger and the MSC biodistribution in the damaged tissue need to be considered.
In conclusion, we dissected several aspects of PK-PD of MSCs and we suggest a new model that underscores the importance of PK and PD for the success of MSC-based therapies that should consider possible bioactive substances and biomarkers to improve the prediction of a clinical dosing regimen with higher efficacy. This work was supported in part by unrestricted grants from Chiesi Farmaceutici S.