Lecture 14: Mesenchymal stem cells - Clinical trials and controversies

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Questions and Answers

What is the primary biochemical process involved in apoptosis?

Inhibition of apoptosis factors

Cellular repair mechanisms

Cellular differentiation pathways

Activation of proteolysis by caspases (correct)

In the context of MSC treatment for GVHD patients, what distinguishes responders from non-responders?

Non-responders had higher initial MSC counts

Responders showed increased stem cell proliferation

Responders had immune cells that induced apoptosis in MSCs (correct)

Non-responders possessed stronger immune responses

What technique was used to label apoptotic MSCs for tracking in vivo?

Cell trace violet fluorescent dye (correct)

Green fluorescent protein

Quantum dot labeling

Cytofluorescent antibody tagging

Which of the following immunosuppressive molecules was NOT mentioned as being expressed by phagocytes that engulfed apoptotic MSCs?

TNF-alpha Signup and view all the answers

What evidence indicated caspase activity and apoptosis of MSCs after their administration in a study?

Increased caspase activity in a mouse model of GVHD Signup and view all the answers

What is a primary reason mesenchymal stem cells (MSCs) are injected during allergic asthma?

To reach and mitigate inflammation primarily in the lungs. Signup and view all the answers

Which cytokine is primarily responsible for recruiting eosinophils to the lungs during allergic asthma?

IL-5 Signup and view all the answers

What paradox is associated with the therapeutic effects of MSCs despite their short lifespan?

Their therapeutic benefits seem to last longer than their lifespan. Signup and view all the answers

What is required of the secreted factors from MSCs for their immunosuppressive effects to be effective?

To maintain a long half-life and act over long distances. Signup and view all the answers

What is the primary action of TH2 cells during an allergic asthma response?

They facilitate B-cell activation and produce specific antibodies. Signup and view all the answers

Which of the following responses best summarizes the potential limitation of MSCs in clinical applications?

They often get trapped in the lungs after injection. Signup and view all the answers

What role does IL-4 play in the allergic asthma mechanism?

It regulates IgE production and B-cell switching. Signup and view all the answers

Why is the mechanism of allergic asthma relevant for studying MSC effects?

Because MSCs localize to the lungs where inflammatory action occurs. Signup and view all the answers

What is the overall outcome of TH2 cytokine activity during an asthma attack?

Increased airway inflammation and mucus production. Signup and view all the answers

Which characteristic is NOT used to categorize mesenchymal stem cells (MSCs)?

Presence of hematopoietic markers Signup and view all the answers

What is the role of IL-5 in the pathology of asthma as observed in the study?

Facilitates eosinophil recruitment Signup and view all the answers

Which of the following is a key observation in MSC-treated asthmatic mice?

Reduced pink goblet cells Signup and view all the answers

Which tissue sources were MSCs isolated from in the study?

Bone marrow, umbilical cord, and adipose tissue Signup and view all the answers

What was a notable result regarding lung inflammation in MSC-treated mice?

Reduction in inflammatory cell presence Signup and view all the answers

What allergen was used to sensitize mice in the asthma model?

Ovalbumin (OVA) Signup and view all the answers

What was the effect of MSC treatment on airway hyperreactivity in asthmatic mice?

It reduced airway hyperreactivity to levels comparable to normal mice. Signup and view all the answers

Which cytokine is known to contribute to airway hyperreactivity and airway function?

IL-13 Signup and view all the answers

What was the nature of the experimental setup used in testing MSCs?

Induction of asthma in a mouse model Signup and view all the answers

Which MSC source resulted in improvement in lung resistance and compliance levels?

All three sources equally improved lung functions. Signup and view all the answers

How did researchers track the localization and survival of injected MSCs?

By incorporating a luciferase gene into MSCs. Signup and view all the answers

What indicates the effective differentiation capability of MSCs according to the study?

In vitro ability to differentiate into various cell types Signup and view all the answers

What happened to the luciferase-expressing MSCs shortly after injection?

Their signal disappeared completely within 2–3 days. Signup and view all the answers

What pathological changes were observed in the lungs of asthmatic mice?

Increase in pink goblet cells Signup and view all the answers

What is suggested about the relationship between MSC apoptosis and patient response to treatment?

Increased MSC apoptosis indicates poor response to treatment. Signup and view all the answers

What type of cells were specifically highlighted for being absent in some regions?

Goblet cells Signup and view all the answers

What is indicated by the increased mucus in asthmatic mice?

It leads to increased resistance in the airways. Signup and view all the answers

Which treatment group demonstrated a significant improvement in dynamic compliance?

Both bone marrow and umbilical cord-derived MSCs enhanced compliance. Signup and view all the answers

What is the primary limitation observed in MSCs following their administration?

Their short survival time in the lungs. Signup and view all the answers

When the MSCs were injected, where did they primarily localize?

To the lungs. Signup and view all the answers

What is a significant uncertainty regarding the use of MSCs in therapy?

The impact of donor MSC rejection on the efficacy of allogeneic MSC therapies is unclear. Signup and view all the answers

What mechanism is suggested to describe MSC functionality rather than engraftment?

Hit-and-run mechanism Signup and view all the answers

What was a common assumption in early studies about MSCs?

MSCs must engraft into tissues to repair damage. Signup and view all the answers

What condition was noted about MSCs during clinical trials based on autopsy findings?

They encountered a pulmonary impasse and did not engraft long-term. Signup and view all the answers

Which of the following describes a bi-directional effect of MSCs on T cells?

MSCs inhibit T cell function while T cell cytokines enhance MSC immunosuppression. Signup and view all the answers

What has been noted about MSCs regarding their lifespan?

They have a limited lifespan and are considered short-lived. Signup and view all the answers

What is one of the primary clinical applications of the immunomodulatory properties of MSCs?

To treat inflammatory conditions. Signup and view all the answers

Study Notes

Mesenchymal Stromal Cells - Clinical Trials and Controversies

MSCs are a part of the HSC niche in bone marrow
Most MSCs are found in perivascular regions of bone marrow, but also in other areas in smaller numbers.
Human MSCs express markers such as STRO-1, CD146, VECAM1, CD271, and CD105
Male MSCs express additional markers such as SCAR1 and PDGF receptor.
BM MSCs give rise to skeletal cells.
MSCs can differentiate into osteoblasts, chondroblasts, adipoblasts, other stromal cells (like fibroblasts)
Bulk stroma vs bona fide (genuine/true) stem cells
Bona Fide Skeletal Stem Cells are isolated and plated at low-density to select for clonogenic or single-sorted cells
These cells form colonies and are transplanted into a mouse to form an ossicle (heterotopic bone).
The formation of an ossicle proves self-renewal and multipotency—making the cells skeletal stem cells.
MSCs used in cell therapy are plated at high-density and selected for plastic adherence.
These preparations contain a small number of skeletal stem cells
The bulk of the MSC preparation are mesenchymal stromal cells; not stem cells.
Skeletal stem cells demonstrate self-renewal and multipotency.
MSCs used in therapy lack the defining properties of a stem cell

ISCT Definition of MSCs

MSCs adhere to plastic in standard culture conditions; an inadequate criterion.
MSCs must express CD73, CD90, and CD105; they must not express hematopoietic markers (CD11b, CD45, CD19, and HLA-DR).
In vitro, MSCs differentiate into adipocytes, osteoblasts, and chondrocytes.

MSCs as Cell Therapy

MSCs are being investigated for various disease treatment.
Earlier studies reveal MSCs do not elicit a strong immune response with anti-inflammatory effects.

MSCs are not immune-privileged

Current studies show MSCs can cause both cellular and humoral allogeneic responses
MSCs are immunogenic and evoke antibody generation.

MSCs and Immune Rejection

MSCs can be rejected by an immune response.
This impacts the clinical efficacy of allogeneic MSC therapies.

MSCs Do Not Engraft

Early trials focused on MSC differentiation into bone or cartilage
Studies assumed MSCs needed to engraft tissue, but the assumption proved incorrect.

MSCs Encounter Pulmonary Impasse

Studies have shown MSCs are trapped in the lungs and short-lived
Autopsy tissues showed no long-term engraftment, nor ectopic tissue formation
MSC function likely occurs via a "hit-and-run" mechanism, not sustained tissue engraftment.

Immunomodulatory Effects of MSCs

MSCs possess potent immunomodulatory properties that can be used clinically to treat inflammatory conditions.
MSCs can modulate the various cells in the immune system.

MSC Response to Inflammatory Signals

MSCs respond to inflammatory signals like interferon-gamma (IFN-γ) and tumor necrosis factor (TNF)
These signals are produced by immune cells
This interaction leads to MSC licensing or activation.

MSC Licensing or Activation

MSC licensing or activation may lead to production of inhibitory factors and growth factors.
Surface molecules and expression levels might also be altered.

Controversies Surrounding MSC Use

There is a distinction between bona fide skeletal stem cells and stromal cells used in cell therapy.
Bona fide skeletal cells are isolated using MSC markers.
These cells can be cultured at low density in plastic and form ossicles.
Stromal cells are cultured at high density.
These cells are infused into patients.

Minimal Criteria for Defining MSCs (Inadequate)

The International Society for Cell Therapy (ISCT) has minimal criteria to define MSCs
Cells must adhere to plastic in standard culture conditions. This is inadequate; as non-clonal connective tissue cells also adhere to plastic.
MSCs must be positive for CD105, CD73, and CD90 and negative for hematopoietic markers.

MSCs and Asthma

MSC treatment reduces asthma indicators (IL-5 and IL-13) in mice treated with OVA (allergen).
Eosinophil levels are reduced in MSC treated mice.

Tracking fate of injected MSCs

A technique involving Luciferase was used to track the fate of MSCs after injection.
MSC localization and survival was analyzed.

MSCs and Apoptosis

Studies show MSCs undergo apoptosis after injection into mice
This impacts treatment effectiveness.
MSC apoptosis may vary patient response
Induction of MSC apoptosis is a predictor of patient response.

Immunosuppressive Effects in Phagocytes

Phagocytes engulf apoptotic MSCs.
There is an up-regulation of immunosuppressive molecules.
Pro-inflammatory molecules like TNF-alpha are downregulated
This can influence therapeutic effects.

Depletion of Macrophages and MSCs

Macrophage depletion eliminates MSC immunosuppressive effects.
This demonstrates a distinct relationship between macrophages, MSCs, and a response.

Mechanisms of MSC Immunomodulatory Effects - Live MSCs

MSC activation through inflammatory cytokines (like interferon gamma and TNF).
Expression of surface molecules required for immune modulation.
Production of anti-inflammatory or immunosuppressive molecules.

Mechanisms of MSC Immunomodulatory Effects - Apoptotic MSCs

Apoptotic MSCs stimulate phagocytes.
Phagocytes upregulate immunosuppressive molecules, downregulate pro-inflammatory molecules.

Differences Between Skeletal Stem Cells and MSCs

Skeletal stem cells derive from tissues such as bone marrow and serve as progenitors of skeletal tissue
MSCs derive from various tissues
Skeletal stem cells effectively function in vivo.
MSCs function more effectively as dying/apoptotic cells
The differences in their function and response to treatment mechanisms highlight areas needing clarification in terms of effective therapies.

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Description

This quiz delves into the clinical trials and controversies surrounding mesenchymal stromal cells (MSCs). It covers their location, markers, differentiation capabilities, and their role in cell therapy. Test your knowledge on the significance and challenges of MSCs in medical science.