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Microenvironmental considerations in the application of human mesenchymal stem cells in regenerative therapies.

Greco SJ, Rameshwar P - Biologics (2008)

Bottom Line: One consideration that poses a formidable task for the successful clinical application of stem cells in new disease models is the impact of the host tissue microenvironment on the desired therapeutic outcome.In this review, we focus on the possible contribution by microenvironmental factors, and how these influences can be overcome in therapies utilizing mesenchymal stem cells (MSCs), such as for graft versus host disease, multiple sclerosis and ischemia among others.Specifically, we examine three ubiquitous microenvironmental factors, IL-1alpha/beta(,) TNFalpha, and SDF-1alpha, and consider how inhibitors and receptor antagonists to these molecules could be applied to increase the efficacy of MSC therapies while minimizing unforeseen harm to the patient.

View Article: PubMed Central - PubMed

Affiliation: Graduate School of Biomedical Sciences.

ABSTRACT
The therapeutic utilization of stem cells has been ongoing for several decades, principally in the form of bone marrow (BM) transplants to treat various hematological disorders and other immune-related diseases. More recently, stem cells have been examined as a potential therapy for a multitude of other diseases and disorders, many of which are currently untreatable. One consideration that poses a formidable task for the successful clinical application of stem cells in new disease models is the impact of the host tissue microenvironment on the desired therapeutic outcome. In vitro, stem cells exist in surroundings directly controllable by the researcher to produce the desired cellular behavior. In vivo, the transplanted cells are exposed to a dynamic host microenvironment laden with soluble mediators and immunoreactive cells. In this review, we focus on the possible contribution by microenvironmental factors, and how these influences can be overcome in therapies utilizing mesenchymal stem cells (MSCs), such as for graft versus host disease, multiple sclerosis and ischemia among others. Specifically, we examine three ubiquitous microenvironmental factors, IL-1alpha/beta(,) TNFalpha, and SDF-1alpha, and consider how inhibitors and receptor antagonists to these molecules could be applied to increase the efficacy of MSC therapies while minimizing unforeseen harm to the patient.

No MeSH data available.


Related in: MedlinePlus

Cartoon depicting the potential effects of an inflammatory microenvironment on mesenchymal stem cell (MSC) therapies. A. An injured tissue, such as a bone fracture, is laden with inflammatory cytokines, such as IL-1α, IL-1β, TNFα, or IL-6, within the microenvironment. MSCs introduced into the microenvironment can respond to the inflammatory stimuli by synthesizing and releasing immunoreactive factors, such as substance P (SP) or other neuropeptides. Excessive production of SP would lead to an exacerbated immune response and infiltration of additional immune cells into the injured tissue. Additionally, the inflammatory stimuli could have an untoward effect on MSC differentiation, for example differentiation into fibroblasts rather than osteoblasts. B. Alternatively, delivery of MSCs together with an inflammatory cytokine antagonist/inhibitor may abrogate immunoreactivity and allow the desired stem cell therapeutic to proceed unhindered.
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f1-btt-2-699: Cartoon depicting the potential effects of an inflammatory microenvironment on mesenchymal stem cell (MSC) therapies. A. An injured tissue, such as a bone fracture, is laden with inflammatory cytokines, such as IL-1α, IL-1β, TNFα, or IL-6, within the microenvironment. MSCs introduced into the microenvironment can respond to the inflammatory stimuli by synthesizing and releasing immunoreactive factors, such as substance P (SP) or other neuropeptides. Excessive production of SP would lead to an exacerbated immune response and infiltration of additional immune cells into the injured tissue. Additionally, the inflammatory stimuli could have an untoward effect on MSC differentiation, for example differentiation into fibroblasts rather than osteoblasts. B. Alternatively, delivery of MSCs together with an inflammatory cytokine antagonist/inhibitor may abrogate immunoreactivity and allow the desired stem cell therapeutic to proceed unhindered.

Mentions: Transplantation of MSCs alone will generate a local immune response and disrupt homeostasis within the tissue milieu by causing release of inflammatory mediators, such as cytokines. The anatomy of the BM is such that MSCs are in direct interaction with immune cells and form synapse-like structures with innervating nerve fibers (Bianco et al 2001). MSCs express receptors for many cytokines and neurotransmitters, thus demonstrating their potential to respond to local microenvironmental changes (Greco and Rameshwar 2007). Excessive cytokine release within the transplantation site could lead to the production of other soluble factors by the MSCs themselves. If these factors are immunoreactive, then other immune cells could infiltrate the tissue and cause an exacerbated immune response, rejection of the transplant or differentiation of the MSCs (Figure 1A). On the other hand, MSCs have been shown to be a potent source of trophic factors (Phinney and Prockop 2007). These findings indicate that MSCs could also be used to aid normal tissue repair, perhaps even more so than in cell replacement. Whether transplanted MSCs cause an immune insult or help repair injured tissues may be difficult to determine unless appropriate models are developed to better predict the outcome. However, if MSCs are found to negatively impact the host microenvironment through exposure to soluble mediators, there are still potential methods to develop effective therapeutics. When considering the example presented in Figure 1A, inclusion of specific cytokine receptor antagonists or inhibitors could suppress the untoward effects of the host microenvironment on the transplanted MSCs, thus leading to defined therapeutic outcomes (Figure 1B). Throughout the remainder of this review, we will address the feasibility of using similar pharmacologic approaches in MSC transplants, while focusing on three ubiquitous microenvironmental factors: IL-1α/β, TNFα, and SDF-1α. Specifically, we will examine how receptor antagonists or inhibitors to these factors, whether federally approved or in development, may limit the potential negative influences of the tissue microenvironment.


Microenvironmental considerations in the application of human mesenchymal stem cells in regenerative therapies.

Greco SJ, Rameshwar P - Biologics (2008)

Cartoon depicting the potential effects of an inflammatory microenvironment on mesenchymal stem cell (MSC) therapies. A. An injured tissue, such as a bone fracture, is laden with inflammatory cytokines, such as IL-1α, IL-1β, TNFα, or IL-6, within the microenvironment. MSCs introduced into the microenvironment can respond to the inflammatory stimuli by synthesizing and releasing immunoreactive factors, such as substance P (SP) or other neuropeptides. Excessive production of SP would lead to an exacerbated immune response and infiltration of additional immune cells into the injured tissue. Additionally, the inflammatory stimuli could have an untoward effect on MSC differentiation, for example differentiation into fibroblasts rather than osteoblasts. B. Alternatively, delivery of MSCs together with an inflammatory cytokine antagonist/inhibitor may abrogate immunoreactivity and allow the desired stem cell therapeutic to proceed unhindered.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2727904&req=5

f1-btt-2-699: Cartoon depicting the potential effects of an inflammatory microenvironment on mesenchymal stem cell (MSC) therapies. A. An injured tissue, such as a bone fracture, is laden with inflammatory cytokines, such as IL-1α, IL-1β, TNFα, or IL-6, within the microenvironment. MSCs introduced into the microenvironment can respond to the inflammatory stimuli by synthesizing and releasing immunoreactive factors, such as substance P (SP) or other neuropeptides. Excessive production of SP would lead to an exacerbated immune response and infiltration of additional immune cells into the injured tissue. Additionally, the inflammatory stimuli could have an untoward effect on MSC differentiation, for example differentiation into fibroblasts rather than osteoblasts. B. Alternatively, delivery of MSCs together with an inflammatory cytokine antagonist/inhibitor may abrogate immunoreactivity and allow the desired stem cell therapeutic to proceed unhindered.
Mentions: Transplantation of MSCs alone will generate a local immune response and disrupt homeostasis within the tissue milieu by causing release of inflammatory mediators, such as cytokines. The anatomy of the BM is such that MSCs are in direct interaction with immune cells and form synapse-like structures with innervating nerve fibers (Bianco et al 2001). MSCs express receptors for many cytokines and neurotransmitters, thus demonstrating their potential to respond to local microenvironmental changes (Greco and Rameshwar 2007). Excessive cytokine release within the transplantation site could lead to the production of other soluble factors by the MSCs themselves. If these factors are immunoreactive, then other immune cells could infiltrate the tissue and cause an exacerbated immune response, rejection of the transplant or differentiation of the MSCs (Figure 1A). On the other hand, MSCs have been shown to be a potent source of trophic factors (Phinney and Prockop 2007). These findings indicate that MSCs could also be used to aid normal tissue repair, perhaps even more so than in cell replacement. Whether transplanted MSCs cause an immune insult or help repair injured tissues may be difficult to determine unless appropriate models are developed to better predict the outcome. However, if MSCs are found to negatively impact the host microenvironment through exposure to soluble mediators, there are still potential methods to develop effective therapeutics. When considering the example presented in Figure 1A, inclusion of specific cytokine receptor antagonists or inhibitors could suppress the untoward effects of the host microenvironment on the transplanted MSCs, thus leading to defined therapeutic outcomes (Figure 1B). Throughout the remainder of this review, we will address the feasibility of using similar pharmacologic approaches in MSC transplants, while focusing on three ubiquitous microenvironmental factors: IL-1α/β, TNFα, and SDF-1α. Specifically, we will examine how receptor antagonists or inhibitors to these factors, whether federally approved or in development, may limit the potential negative influences of the tissue microenvironment.

Bottom Line: One consideration that poses a formidable task for the successful clinical application of stem cells in new disease models is the impact of the host tissue microenvironment on the desired therapeutic outcome.In this review, we focus on the possible contribution by microenvironmental factors, and how these influences can be overcome in therapies utilizing mesenchymal stem cells (MSCs), such as for graft versus host disease, multiple sclerosis and ischemia among others.Specifically, we examine three ubiquitous microenvironmental factors, IL-1alpha/beta(,) TNFalpha, and SDF-1alpha, and consider how inhibitors and receptor antagonists to these molecules could be applied to increase the efficacy of MSC therapies while minimizing unforeseen harm to the patient.

View Article: PubMed Central - PubMed

Affiliation: Graduate School of Biomedical Sciences.

ABSTRACT
The therapeutic utilization of stem cells has been ongoing for several decades, principally in the form of bone marrow (BM) transplants to treat various hematological disorders and other immune-related diseases. More recently, stem cells have been examined as a potential therapy for a multitude of other diseases and disorders, many of which are currently untreatable. One consideration that poses a formidable task for the successful clinical application of stem cells in new disease models is the impact of the host tissue microenvironment on the desired therapeutic outcome. In vitro, stem cells exist in surroundings directly controllable by the researcher to produce the desired cellular behavior. In vivo, the transplanted cells are exposed to a dynamic host microenvironment laden with soluble mediators and immunoreactive cells. In this review, we focus on the possible contribution by microenvironmental factors, and how these influences can be overcome in therapies utilizing mesenchymal stem cells (MSCs), such as for graft versus host disease, multiple sclerosis and ischemia among others. Specifically, we examine three ubiquitous microenvironmental factors, IL-1alpha/beta(,) TNFalpha, and SDF-1alpha, and consider how inhibitors and receptor antagonists to these molecules could be applied to increase the efficacy of MSC therapies while minimizing unforeseen harm to the patient.

No MeSH data available.


Related in: MedlinePlus