Abstract

Mesenchymal stem/stromal cells (MSCs) are increasingly used therapeutically via intravenous administration due to their efficacy in tissue repair and anti-inflammatory roles. However, comprehensive data on MSC biodistribution, target structures, and migration mechanisms remain sparse. This review explores current hypotheses regarding MSC tissue targeting, covering both preclinical and clinical studies.

Background

In the 1970s, Friedenstein et al. [1] first reported the localized application of culture-expanded bone marrow stroma-derived fibroblastic cells, initiating ectopic hematopoiesis under the kidney capsule. Caplan’s group later defined MSCs as multipotent cells capable of differentiating into various tissues, highlighting their regenerative potential in bone and cartilage [2–4]. Initial studies primarily focused on site-specific effects without addressing biodistribution.

By 2000, interest grew in intravenous MSC application, spurred by Horwitz’s pivotal studies in children with osteogenesis imperfecta [5]. These studies demonstrated MSC efficacy in bone marrow deficiency, suggesting MSC homing to bone sites. Subsequent studies further explored intravenous MSC therapy, employing diverse labeling techniques to track MSC migration across tissues [7–11].

Establishment of Methods to Track Intravenously Administered MSCs

Post-2000, numerous studies in animals and humans utilized various labeling methods to track intravenously administered MSCs. Techniques included radioactive labels, fluorescent dyes, contrast agents, and reporter genes [7–11]. Despite these advancements, tracking methods often only detected short-term MSC homing and did not confirm cell viability. Studies consistently showed initial MSC accumulation in lungs post-injection, followed by distribution to liver and spleen [12].

Human studies, such as those by Koç et al. [13] in mammary carcinoma patients and others in liver cirrhosis patients [14], validated animal findings, confirming MSC presence in blood and major organs. Notably, lung accumulation decreased over time, contrasting with increasing signals in liver and spleen up to 10 days post-administration [14].

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Expression of Cell Adhesion Molecules by MSCs: Basis for Interaction with Endothelial Cells and Tissue-Directed Extravasation

In theory, the interaction of transplanted MSCs with endothelial cells hinges on adhesion molecules present on MSC surfaces and corresponding counter-receptors on endothelial cells. Here’s a breakdown of the current understanding:

Adhesion Molecule Expression by MSCs

Human MSCs (hMSCs) notably exhibit deficiencies in receptor binding to selectins and their ligands. Key findings include:

• Lack of L-selectin expression.
• Non-functional CD44 as an E-selectin ligand [15].
• Binding to P-selectin via a fucosylated ligand, though not P-selectin glycoprotein ligand (PSGL)-1 [16].
• Enzymatic fucosylation of CD44 by Thankamony and Sackstein enhances MSC binding to endothelial E-selectin, facilitating MSC rolling and extravasation into bone marrow sites [17].

Integrin Expression

MSCs express alpha4beta1 (VLA-4) and alpha5beta1 (VLA-5) integrins, critical for their interaction with endothelial cells and tissue-specific homing [15, 16, 18–20].

Chemokine Receptors

MSCs also express chemokine receptors such as CXCR4, which plays a pivotal role in homing and mobilization of hematopoietic cell types [12, 19, 20].

Summary

These insights underscore MSCs’ challenges in expressing and utilizing adhesion receptors for effective extravasation and tissue-specific homing, akin to leukocyte populations.

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Table 1: Common Themes in MSC Biodistribution Research

Theme	Targeted Tissues (Possible Mechanism)	References
Increased homing after intra-arterial delivery compared with intravenous delivery?	Kidney, Joints, Stroke, Other tissues	[30–34]
Side effects of intra-arterial versus intravenous delivery?	Incorporation into vessel wall, Obstruction of microvessels, Vascular occlusion	[23, 35, 38, 39]
Targeting of vessel wall and vessel-associated tissues?	Lungs, Lymph nodes, Intestine	[47]
Targeting of tissues for regeneration	Myocardium, Beta1 integrins, CCL2 (monocytes), Kidney, Gut and liver, Skin, CCL21, JAM-A, Brain, P/E selectin (CD44), CXCR4/flk-1/EPO-R	[18, 30, 44, 48–55, 56–75]
Homing to bone marrow	Bone marrow	[76–81]
Biodistribution to the immune system	Macrophages, Dendritic cells, T cells, Unknown target cells, Idoleamine desoxygenase, Prostaglandin E2	[37–43]
Elimination mechanisms?	Antibody formation, Phagocytes	[6, 102]
Influence of radiation on homing?	Increased in brain, heart, bone marrow, muscles	[43, 82]
Homing in malignancies?	Tumor, Mediated by CCL25, Mediated by sodium iodide symporter under the control of RANTES/CCL-5 promoter, Homed MSCs form tumor-associated fibroblasts	[83–92]
Formation of microvesicles	Contribution to/be part of MSC biodistribution, Mediated by horizontal transfer of microRNAs	[14, 63, 93–97]

In many of the earlier studies

In many of the earlier studies, the target sites as well as the molecular mechanisms governing the interactions of MSCs with the local environment after transplantation (e.g., endothelial cells, target tissue), such as adhesion molecules or signaling mechanisms, were either not addressed or were analyzed only to a minor degree. Moreover, MSCs were often evaluated by microscopy, a method relatively prone to artifacts. Many studies also did not quantify the numbers of MSCs in target or other tissues. Likewise, only few studies reported on the size of the identified MSCs. Despite this lack of information, other themes have emerged, especially research on cues that may regulate the biodistribution of systemically applied MSCs; these include first pass tissues, specifically the lungs, inflammation, irradiation, sites of hypoxia or repair, and cancer (Table 1). As a result, concepts have been raised which imply an ability of MSCs to migrate to specific sites—e.g., MSCs as an “injury drugstore” for several acute clinical situations [21, 22].

First-line accumulation of intravenously administered MSCs in the lungs

The first hurdle for intravenously transplanted MSCs is the lung capillary bed. After culture expansion, MSCs are relatively large cells with an estimated average size of around 30 µm in suspension (ranging from 16–53 µm) [23]. Their size may also vary depending on the osmolarity of the culture media, passage number, and/or cell density during seeding as well as general culture conditions (two-dimensional versus three-dimensional culture). In comparison with MSCs, hematopoietic stem cells have a much smaller diameter, ranging from 4–12 µm depending on the subfraction analyzed [24, 25]. Therefore, obstructive events during lung passage are expected after intravenous administration of MSCs. Lee et al. [26] presented a kinetic study of MSCs accumulating in murine lungs in which up to 80 % of injected cells were found in the lungs within a few minutes after injection. Moreover, formation of emboli in lung vessels was noted. The MSC signal (an Alu sequence DNA marker) fell exponentially, with a half-life of about 24 h and practically complete disappearance after 4 days [26]. Barbash and colleagues [10] confirmed the detection of the overall MSC load in the lungs using 99mTc-labeled MSCs in a rat model with induced myocardial infarction. Murine MSCs also showed deleterious effects in mice, including post-injection lethality, which was not the case after administration of hMSCs [27]. Interaction of human or murine MSCs with lung endothelial cells was dependent on the suspension medium in which the transplanted cells were administered [27]. Adhesion of the MSCs to endothelial cells was found to involve the integrin ligand vascular cell adhesion molecule (VCAM)-1. When comparing MSCs with mononuclear cells from bone marrow, neural stem cells and multipotent adult progenitor cells, Fischer et al. [28] found that MSCs showed the highest interaction with lung endothelia, which could be inhibited by pretreatment with anti-CD49d antibody. In a study by Kerkelä et al. [29], adhesion of MSCs to lung tissue (probably endothelial cells) was dependent on the enzyme treatment used during harvesting of confluent MSCs in culture before transplantation; after treatment with pronase, MSCs more readily cleared the lungs and could be found in other tissues compared with trypsinization treatment. Taken together, these data indicate an active role of the adhesion molecules VLA-4/VCAM-1 on MSCs/endothelial cells during interaction of MSCs with lung tissue. It remains to be clarified, however, whether this is a passive or active process. Also, relatively little is known about possible adhesion molecules other than VLA-4/VCAM-1 which may be operative in the interaction of MSCs with endothelial cell surfaces in the lung. This includes the fucosylation of CD44 to HCELL, a highly active E-selectin ligand on MSCs, which is relevant in bone marrow endothelia but seemingly did not affect lung interactions [15].

In summary, presently there is strong evidence that accumulation of MSCs in the lungs is a key determining factor for their biodistribution. The major adhesion molecule involved seems to be VLA-4/VCAM1. Still, it is not clear to what degree the findings in animal studies are quantitatively transferable to humans (Table 1).

Biodistribution of MSCs after intra-arterial versus intravenous administration

Studies comparing intra-arterial and intravenous application of MSCs have demonstrated a major association between intravenous application and retention of MSCs in the lungs, and their increased accumulation in therapeutic target tissues after intra-arterial injection. Walczak et al. [30] in a rat transient ischemia stroke model applied two independent detection methods (magnetic resonance imaging and Doppler flowmetry). They demonstrated that higher cerebral engraftment rates are associated with impeded cerebral blood flow, and that intra-arterial delivery may be advantageous in ischemic stroke to deliver MSCs to the site of injury. Mäkelä et al. [31] compared intra-arterial and intravenous administration of MSCs labeled with 99mTc, and also found that the intra-arterial transplantation route has a positive impact on the biodistribution of bone marrow-derived MSCs (BM-MSCs) to peripheral tissues. They found that intra-arterial transplantation decreased the deposition of BM-MSCs in the lungs and increased uptake in other organs, especially in the liver. In a study looking at human adipose tissue-derived MSCs in SCID mice, Toupet et al. [32] showed that 15 % of intra-arterially injected MSCs accumulate in inflamed joints during the first month, and 1.5 % over a longer term of >6 months, also favoring intra-arterial over intravenous application for, in their case, anti-inflammatory MSCs. Therapeutic effects of MSCs in kidney have been generally achieved after intra-arterial delivery [33, 34]. Although more studies will be needed, these data suggest that the intra-arterial route of administration is effective in avoiding pulmonary entrapment of BM-MSCs, and may thus improve the biodistribution and bioavailability of transplanted MSCs in clinically relevant tissues for, e.g., tissue repair.

Interactions of MSCs with the blood vessel wall: integration into the vessel wall or transmigration?

As described above, the majority of intravenously injected MSCs are generally detected in the lungs, and in no other tissue at comparable numbers even at later time points. Some groups asked whether MSCs may directly target vessels or perivascular tissue and investigated the fate of MSCs in and around blood vessels. These studies followed the cells using intravital microscopy and histologic examination in different tissues after intra-arterial [23, 30, 35] administration. In the cremaster muscle intravital microscopy model, Furlani et al. [23] observed that the microcirculation was disturbed, with some MSCs obstructing small vessels. In addition, pulmonary emboli were found. Toma et al. [35] also observed occlusion of microvessels and entrapment of the injected MSCs. Moreover, they observed stable integration of some transplanted cells into the vessel wall. Cui et al. [36] reported a risk of vascular occlusion in their rat stroke infarction model after intra-arterial injection, pointing to the fact that local intravasal entrapment of MSCs may frequently occur, and MSCs may obstruct the microcirculation. Currently, however, we lack conclusive data that MSCs that are entrapped in capillaries and/or are incorporated into the vessel wall or adjacent to endothelial cells would relocate (i.e., “home”) to their main tissue of origin, pericytes.

Transplanted MSCs interact with cells of the immune system

Transplanted MSCs have been shown to rapidly interact with immune cell types, which are—at least in part—present also in the bloodstream. In a lung sepsis model, Nemeth et al. [37] observed that MSCs co-localize with lung-resident macrophage cells and induce them to produce anti-inflammatory interleukin (IL)-10 via release of prostaglandin E by MSCs as part of their therapeutic effect. Chiesa et al. [38] showed that interstitial dendritic cells (DCs) decrease their physiological migration from skin to lymph nodes rapidly after intravenous administration of MSCs. They describe that MSCs inhibit Toll-like receptor (TLR)-4-induced activation of DCs, which results in the inhibition of cytokine secretion by DCs, downregulation of adhesion molecules involved in the migration of DCs to the lymph nodes, suppression of DC antigen presentation to CD4+ T cells, and cross-presentation to CD8+ T cells. Akiyama et al. [39] demonstrated that both human and murine MSCs can induce immune suppression by attracting and killing autoreactive T cells through FasL, thereby stimulating transforming growth factor beta production by macrophages and generation of regulatory T cells. The interaction has been shown to involve the secretion of MCP-1 by MSCs. The dying T cells in turn activate macrophages to produce transforming growth factor beta, thus stimulating regulatory T cells and promoting immune tolerance. Possibly, the secretion of anti-inflammatory protein TSG-6 by activated MSCs, which

Potential Mechanisms of Elimination of MSCs from the Circulation

Immune Responses and Antibody Formation

The interaction between transplanted MSCs and immune system cells often triggers xenogeneic and allogeneic immune responses. This can lead to the formation of antibodies or T-cell responses against MSCs, making them undetectable upon subsequent administration in patients [6]. Notably, anti-fetal calf serum antibodies have been documented in patients unresponsive to allogeneic MSC applications [6].

Lung Trapping and Systemic Pathways

Despite efforts to trace transplanted MSCs, they are frequently undetectable or only a small fraction is identifiable. This underscores the potential role of the lung as a “first-pass” tissue and suggests that lung trapping might contribute significantly to the elimination of MSCs from the circulation. Moreover, systemic pathways involved in eliminating MSCs in humans likely play a role in their barely detectable long-term engraftment.

Tissue Repair Signaling and MSC Migration

Myocardial Infarction

In myocardial infarction models, MSC migration is facilitated through the VLA-4/VCAM receptor axis. Studies show that pre-treatment of MSCs with TNF-1alpha enhances their migration via VCAM-1, suggesting a role for beta1 integrins in this process [48]. Additionally, chemokine receptors like CXCR4 influence the homing of MSCs to ischemic myocardial tissue [49].

Kidney Damage

Clinical trials and animal studies have highlighted MSCs’ potential in renal disease therapy. Intravenous administration of MSCs has shown promise in reducing rejection rates and improving renal function post-transplantation [56, 57]. Mechanistically, MSCs aid in repairing the glomerular barrier and mitigating tubular injury in various models of kidney damage [60, 61].

Liver Damage

In liver cirrhosis, MSCs have been observed to migrate to damaged areas, although the mechanisms are not fully elucidated. Studies suggest involvement of corticosteroids and the SDF-1/CXCR4 axis in MSC migration during liver fibrosis [65]. Radioimaging studies have shown gradual accumulation of MSCs in the liver and spleen post-infusion [14].

Gut and Skin

MSCs’ presence has been detected in inflammatory bowel disease models, indicating their ability to home to gut tissues affected by inflammation [67]. Similarly, studies on wound repair have shown MSCs’ potential to differentiate into skin cells, though their efficacy varies [44].

Brain

Research in stroke models demonstrates that MSCs migrate to ischemic brain tissue, delivering neurotrophic factors and modulating microglial activity [72, 73]. Chemokine receptors like CXCR4 play a role in MSC recruitment to inflamed brain areas [74].

Homing of MSCs to Bone Marrow

Engraftment of MSCs in bone marrow depends on specific conditions, such as niche availability. While prolonged culture may impair MSC engraftment in classic bone marrow transplantation, certain deficiencies in recipients may facilitate MSC incorporation [76–80]. Studies indicate that MSCs can mediate stromal engraftment in deficient hosts, contributing to hematopoietic environments [81].

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Potential Mechanisms of Elimination of MSCs from the Circulation

A critical aspect of MSC transplantation involves their interaction with the immune system, both in animal models and humans. Transplanted MSCs can induce xenogeneic and allogeneic immune responses, leading to antibody formation or T-cell responses against them [6]. This immune reaction often results in the failure to detect transplanted MSCs upon repeated administration, particularly when cultured in media containing fetal bovine serum [6]. Studies indicate that anti-fetal calf serum antibodies can develop in patients who do not respond to repeated MSC applications [6]. The elimination mechanisms of xenogeneic MSCs in animals parallel those seen in allogeneic settings.

Despite the identification of several target tissues for MSCs, little data exist on their final destinations or the routes of their elimination after systemic administration. The inability to detect transplanted MSCs or their minimal presence suggests the lung might act as a primary tissue for initial MSC trapping and possibly plays a role in their elimination. Conversely, the systemic pathways responsible for eliminating transplanted MSCs in humans may lead to their barely detectable long-term engraftment.

Influence of Irradiation on Migration and Biodistribution of MSCs

In a murine study, Francois et al. [43] demonstrated that both total body irradiation and local irradiation significantly alter the distribution of intravenously infused hMSCs in NOD/SCID mice compared to untreated controls. Non-irradiated control animals showed minimal presence of infused hMSCs, predominantly in the lung, bone marrow, and muscles. However, mice subjected to total body irradiation exhibited increased absolute numbers of hMSCs in the brain, heart, bone marrow, and muscles. Moreover, selective irradiation of limbs or the abdomen resulted in enhanced engraftment of hMSCs in the exposed skin or muscles compared to total body irradiation alone, indicating both local and systemic effects on MSC engraftment. The study did not investigate long-term engraftment effects.

Sémont et al. [82] investigated the engraftment and efficacy of transplanted MSCs in an immunodeficient mouse model of radiation-induced gastrointestinal tract failure. They observed accelerated recovery in mice receiving hMSCs, characterized by decreased apoptosis of epithelial cells and increased proliferation in the small intestinal mucosa. Despite these benefits, significant amounts of transplanted MSCs were not detected.

A Special Case: Migration and Engraftment of MSCs into Tumors

Tumor-associated fibroblasts, derived from the MSC pool, are integral components of the microenvironment in various solid tumors [83, 84]. Tumor tissue represents a target for intravenously injected MSCs due to their tumor tropism. Experimental studies have reported both beneficial and adverse effects of MSC migration into tumor areas. For instance, Beckermann et al. [85] observed migration of MSCs into areas adjacent to vessel walls in human pancreatic tumors in immunodeficient mice. Additionally, Alieva et al. [86] tracked adipose tissue-derived MSCs in a glioblastoma model, demonstrating their incorporation and subsequent elimination upon gancyclovir administration, leading to tumor regression. These studies underscore the potential utility of MSCs in targeting tumors using approaches like suicide transgene therapy.

Recent Developments: Exosomes, Microparticles, and MSCs

MSCs have the capacity to produce exosomes, small membrane vesicles that play critical roles in mediating therapeutic effects. Exosomes derived from MSCs have been implicated in various target tissues, such as tubular cells in acute kidney injury and post-traumatic brain injury recovery [63, 93, 94]. These vesicles contain signaling molecules that facilitate MSC-mediated therapeutic effects through horizontal transfer mechanisms. Recent studies, such as Kordelas et al. [98], have demonstrated the therapeutic potential of MSC-derived exosomes in treating severe graft-versus-host disease, highlighting their expanding role in regenerative medicine.

Summary: Possible Interactions of MSCs within the Circulatory System and Their Biodistribution

MSCs interact dynamically within the bloodstream, influencing their biodistribution and interactions with the immune system. These interactions include modulation of T-cell responses, evasion of NK cell cytoxicity, and potential triggers of inflammatory responses upon their introduction into the bloodstream [46, 99, 102]. Understanding these interactions is crucial for optimizing MSC-based therapies and enhancing their therapeutic efficacy in various clinical settings.
 

Conclusion

The fate of intravenously injected MSCs remains a puzzle, as evidenced by limited detection in preclinical animal studies and human trials. Numerous questions persist, such as the nature of interactions between MSCs and host cells upon infusion into the bloodstream, the clearance pathways for non-migrating MSCs, and the relevance of intact MSCs in observed therapeutic effects.

Further comprehensive analysis using animal disease models is essential to elucidate the roles of mediators like exosomes, signaling proteins, and microRNAs. These investigations will advance our understanding of MSC biodistribution, migration, homing mechanisms, and the underlying mechanisms of their therapeutic benefits. Insights gained from these studies hold promise for refining MSC-derived therapies and developing new therapeutic strategies.

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