Given the ability of MSCs to differentiate into osteoblasts, chondrocytes, and adipocytes in culture, many investigators have proposed that MSCs are stem cells or progenitors that give rise to specialized mesodermal cell lineages during development or throughout the process of tissue regeneration.
Indeed, MSCs present in some tissues could be multipotent and directly perform stem cell—like functions, although in vivo data are lacking. It is more likely, however, that MSCs indirectly facilitate endogenous cellular mechanisms that result in tissue repair and regeneration, giving the impression of stem cell—like activity. MSCs are also known to exert strong immunosuppressive activity on the adaptive and innate immune systems.
Indeed, the immunomodulatory properties of MSCs present clinical advantages in treating and preventing GVHD, as well as promoting tissue repair and engraftment during hematopoietic cell transplantation HCT. In this review, we describe in vitro, in vivo, and clinical studies in which MSCs have been applied as immunomodulatory cell therapies during HCT to prevent and treat GVHD, repair damaged tissue, and facilitate hematopoietic stem cell engraftment Figure 1.
A variety of MSC tissue sources are being explored for ex vivo expansion, including bone marrow, adipose, umbilical cord, and placenta. Clinical application during HCT includes preventing and treating GVHD, repairing tissue damaged from the conditioning regimen, and facilitating hematopoietic cell engraftment. MSCs are obtained for research and clinical studies from an array of tissue sources.
Viable MSCs have been isolated from bone marrow, adipose tissue, amniotic membrane and fluid, placental and fetal tissues, umbilical cord tissues, endometrium, blood, and synovial fluid.
However, MSCs isolated from bone marrow are most commonly studied clinically. Upon isolation, MSCs must be expanded in culture ex vivo, because cell numbers are very limited in human tissues. Although serum-free media for tissue culture of MSCs is under development, current protocols require some serum supplementation.
For ex vivo expansion of MSCs in animal studies, fetal bovine serum or human platelet lysate may be used. The impacts of cryopreservation and freeze-thaw cycles on MSC immunomodulatory activity remain speculative. These immunomodulatory properties can effectively regulate the adaptive and innate immune responses, although additional research is required to understand which mechanisms occur in vivo.
Most likely, not all immune-suppressive activity of MSCs is relevant to every clinical setting. A summary and comparison of proposed immunomodulatory mechanisms of MSCs in studies reviewed herein. MSCs have also been implicated in the suppression of B lymphocytes. MSCs interact with the innate immune system, specifically by signaling with monocytes and macrophages to promote pro- or anti-inflammatory pathways and repair damaged tissues.
There is also evidence that inactive apoptotic MSCs and MSCs engulfed by phagocytes eg, monocytes or inactivated via recipient cytotoxic cells promote host immunosuppressive mechanisms in vitro and in mouse models.
Stage 2 ensues after the hematopoietic graft has been infused when the adoptively transferred donor T cells are activated by host antigen-presenting cells, which is potently promoted by the inflammatory cytokines resulting from the injured tissues. In stage 3, activated donor T cells target host tissue and initiate alloreactive cytotoxic mechanisms. In stage 1, MSCs may migrate to sites of inflammation and limit tissue injury and hasten healing by their tissue-regeneration activity.
In stage 2, MSCs may traffic to sites of alloactivation and inhibit the proliferation of activated T cells. In stage 3, MSCs may migrate to sites of donor T-cell host-tissue interaction and inhibit the immune response. For established GVHD, MSCs could migrate to the sites of host tissue, target and suppress alloreactive T-cell cytotoxicity, and promote tissue healing. MSCs migrate to these sites of inflammation where they may limit tissue damage and promote healing and tissue regeneration.
Third, activated donor T cells target host tissue immune injury. Although less is known about how MSCs act in the third stage, MSCs could migrate to sites of graft-versus-host interactions and inhibit the local immune response. CTL, cytotoxic T lymphocyte. Given that interest in clinical applications began with hematologists who focus on HCT, it is not surprising that GVHD has commanded considerable attention.
Indeed, preclinical animal studies have presented mixed results, underscoring the importance of appreciating the nuances of a specific model and experimental conditions.
A consistent finding among animal and clinical studies is that MSC infusions seem to be safe, laying the foundation for the plethora of clinical trials. No MSC-related toxicity was associated with these infusions; 30 patients demonstrated a complete response to treatment, including increased survival, and 9 showed improved symptoms. Four of the 22 adult patients suffered from cGVHD and did not respond to treatment, 3 of whom had died 3 months into the study.
Although the immunologic role of BM-MSCs in situ has not been fully elucidated, DSCs physiologically reside at the maternal-fetal interface and contribute to the immunologic barrier preventing maternal cell—mediated immunity from attacking the fetus.
Table 2 summarizes relevent clinical trials. All MSCs were from a third-party donor and were expanded, cultured, and prepared according to good manufacturing process standards. Immune phenotyping proving MSC expression profile was performed per Horwitz et al. Interestingly, the efficacy of MSCs as a treatment for aGVHD appears to be greater in pediatric patients than in adult patients, although there is currently no experimental evidence to provide insight into the underlying mechanism of this observation.
Although off-the-shelf MSC products have demonstrated efficacy, the level of efficacy is variable between studies, suggesting that further research is required to determine the optimal cell dosage, treatment timeline, patient age, and disease presentation to treat.
Moreover, additional clinical research is needed to define the long-term effectiveness, the therapeutic mechanism of action in vivo, and the efficacy of different MSC tissue sources. Finally, placenta-derived DSCs present a promising therapy for aGVHD and should be investigated extensively in randomized clinical trials. MSCs act directly on the immune system, and their regenerative potential could play a role in repairing tissue damage during HCT, because such injury is the first stage in the progression of aGVHD Figure 2.
MSCs are known to traffic to damaged and inflamed tissue sites, and it has been suggested that they may promote repair of damaged tissues or tissue regeneration. Similarly, Hassan et al reported that HC may be successfully treated with third party BM-MSCs, noting gross hematuria receding a median of 3 days postinfusion.
Gross hematuria subsided after a median of 3 days in 5 of the 7 HC patients, with the remaining 2 patients dying of multiorgan failure. Both patients with pneumomediastinum responded completely to treatment; the patient experiencing perforated colon and peritonitis initially responded to treatment, but after remission, a second infusion again reversed the disease.
Although the notion of tissue injury is an established component of GVHD pathogenesis, and the regenerative actions of MSCs have been amply demonstrated, the regenerative functions of MSCs may take on greater significance.
The idea of tissue tolerance predicts that this would mitigate the severity of GVHD. Although not yet explored, the mechanisms of MSC efficacy as prophylaxis and treatment of aGVHD may, in part, involve modulation of tissue tolerance. In animal systems, it has been reported that MSCs facilitate HSC engraftment and reconstituting of hematopoiesis by secreting cytokines, eg, granulocyte-macrophage colony-stimulating factor and IL However, the kinetics of neutrophil recovery was not observed.
Graft failure after autologous HCT is an especially serious complication; MSC therapies have demonstrated the potential to rescue hematopoiesis after autologous HCT graft failure. MSCs are unambiguously immunosuppressive in vitro, as well as in preclinical animal models and clinical studies. However, the most appropriate clinical indications and the extent of therapeutic benefit remain to be firmly established. Rather, MSCs should be considered a new agent that may have important advantages compared with current therapeutic options.
The cornerstone of MSCs as a cellular therapy may be the combination of demonstrated efficacy and the outstanding clinical safety profile. Indeed, immune-suppressive activity without significant toxicity is a major advantage over pharmaceuticals, such as calcineurin inhibitors and JAK inhibitors, and could justify more widespread use in patients. Even extracorporeal photopheresis, with relatively few associated toxicities, requires placement of a dialysis-quality central venous catheter and several hours of treatment.
Moreover, unlike many other immune-suppressive agents, there is no evidence that MSCs increase the risk of leukemic relapse or opportunistic infection. The development of MSCs as therapy has seen many setbacks; nonetheless, recent scientific advances and well-designed clinical trials underscore the unrealized therapeutic potential and suggest that MSCs will become an important component of our armamentarium in HCT.
To fulfill this prediction, 3 great challenges must be addressed. First, the basic science and complete mechanism of specific therapeutic activity must be understood.
MSCs exhibit many potentially immune-modulating activities; however, it is unlikely that the cells use all possible pathways in all settings. Hence, the distinct mechanism of an explicit activity, eg, treatment of GVHD or stimulating tissue repair, must be elucidated.
Such scientific knowledge will inform the development of greatly needed clinically relevant potency assays, as well as strategies to enhance MSC potency, including genetically modifying MSCs, , and goals to optimize manufacturing protocols, all of which are critical elements of ultimate success.
The second challenge is translational science: investigators must understand the activity of MSCs in patients. Every phase I and II clinical trial should be accompanied by an extensive battery of correlative laboratory studies to understand the impact of MSCs in human subjects.
Moreover, it is especially important that these studies seek to understand why MSCs are seemingly more effective in children and whether the mechanisms can be leveraged to increase MSC efficacy in adults. The third major challenge is clinical science: well-designed adequately powered clinical trials with appropriate study populations and relevant and reasonable end points should be implemented. The Burnhams homeschooled all five of their children.
They run a jewelry business in Arlington called "Who's Phil? Phil Burnham manages the business side of the group, playing multiple roles of manager, go-between with the record company people and other members of the music industry, and attends all of their concerts and performances. He also handles the more routine tasks of selling the group's merchandise and driving them everywhere on the tour bus. He logged more than 12, miles behind the wheel during the last one.
Meanwhile, Marianne Burnham keeps her eye on making sure the three boys don't get blown off-course by the sometimes unpredictable nature of the professional music business, she said. She'll stay at home with the couple's two daughters and mind the jewelry business while the boys are out on the road during their upcoming tour, she said.
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