Mechanotransduction in Disease and Microenvironment Effects

Disease

Any harmful deviation from the normal structural or functional state of an organism, generally associated with certain signs and symptoms and differing in nature from physical injury.

Microenvironment

A small, specialized area that surrounds and supports cells and tissues.

Aberrant

Deviating from the usual or natural type: atypical, abnormal.

Rheumatoid Arthritis (RA)

Cause: Autoimmune attack on synovial joints. ECM Destruction: Chronic inflammation leads to excessive MMP activity, breaking down collagen, fibronectin, and hyaluronic acid in the joint ECM.

Chronic Obstructive Pulmonary Disease (COPD)

Cause: Long-term smoking, air pollution, genetic factors (e.g., α1-antitrypsin deficiency). ECM Destruction: Elastin and collagen degradation in alveolar walls due to elastase overactivity, leading to emphysema and airway collapse.

Aortic Aneurysm

Cause: Chronic hypertension, genetic disorders (Marfan syndrome, Ehlers-Danlos syndrome). ECM Destruction: Weakening of elastin and collagen fibers in the arterial wall due to increased MMPs and inflammatory cytokines.

Atherosclerosis

Cause: High cholesterol, hypertension, smoking, diabetes. ECM Overproduction: Plaques contain excessive ECM proteins (collagen, elastin, proteoglycans) deposited by vascular smooth muscle cells. Calcification further stiffens arteries.

Pulmonary Fibrosis (Idiopathic Pulmonary Fibrosis, IPF)

Cause: Chronic lung injury (environmental toxins, infections, acid reflux). ECM Overproduction: Excessive deposition of collagen (Type I and III) and fibronectin by activated fibroblasts (myofibroblasts), leading to stiffened lung tissue.

Diabetic Cardiomyopathy

Cause: High blood sugar increases oxidative stress and inflammation in the heart. ECM Changes: Excessive collagen I and III deposition → myocardial fibrosis. Reduced elastin → loss of flexibility, leading to heart failure with preserved ejection fraction (HFpEF).

Diabetic Foot Ulcers

Cause: Hyperglycemia damages small blood vessels and reduces fibroblast function. ECM Changes: Reduced collagen I and fibronectin synthesis → slow wound healing. Excessive MMP activity degrades ECM too quickly, preventing proper tissue repair.

Mechanotransduction Connection

Increased ECM stiffness activates fibroblasts via YAP/TAZ. TGF-β signaling drives fibroblast differentiation into myofibroblasts, worsening fibrosis.

ECM Destruction

Destruction of the ECM is present in nearly all diseases.

ECM Overproduction

Some diseases alter the ECM in different ways in different areas of the body.

Impact of Mechanotransduction

How disease can impact the microenvironment (ECM, Cell function) and how these all translate into mechanotransduction.

Prevalence and Incidence Rate

The frequency of a disease in a population, often expressed as a percentage or ratio.

Sex Based Differences

Variations in disease prevalence, incidence, and outcomes based on biological sex.

Treatment Outcomes

The outcomes/success rates with current treatment methods.

Patient Outcomes Improvement

How could we better study/treat/test/improve patient outcomes.

Homework Goals

Understanding the disease, its causes, prevalence, progression, impact of mechanotransduction, and treatment options.

Diabetes

Affects multiple organ systems through dysregulated ECM remodeling, with stiffening (fibrosis) in some tissues and degradation (poor wound healing, vascular damage) in others.

ECM Remodeling

The process by which the extracellular matrix is altered, impacting various cellular behaviors and disease progression.

Cancer

Involves ECM remodeling for tumor growth and metastasis.

Pancreatic Cancer

Characterized by desmoplasia and ECM stiffening.

Desmoplasia

Excessive ECM deposition (fibronectin, collagen I/III) creates a dense, fibrotic barrier around the tumor.

MMPs

High levels of matrix metalloproteinases (MMP-2, MMP-9) degrade ECM locally, allowing tumor invasion.

Mechanotransduction

Stiff ECM activates integrins and FAK signaling, promoting tumor growth.

ECM Topography

Altered ECM topography enhances cell migration and metastasis.

Dense ECM

Limits drug delivery, reducing chemotherapy effectiveness.

Cell Proliferation

Normal function involves controlled cell division to maintain tissue homeostasis, but disease can lead to uncontrolled proliferation.

Breast Cancer

An example of disease impacting cell proliferation through loss of cell cycle regulation due to mutations.

Cell Death & Apoptosis

Normal function involves programmed cell death to remove damaged or unneeded cells; disease can alter this process.

Neurodegenerative Disease

Example: Alzheimer's, where misfolded proteins trigger excessive neuronal apoptosis.

Cell Migration & Invasion

Normal function involves movement for wound healing and immune response; disease can impair or enhance this migration.

Metastatic Cancer

Example: Pancreatic Cancer, where tumor cells hijack MMPs to enhance migration.

Cell Adhesion & Communication

Normal function involves attachment to ECM and neighboring cells; disease can alter this function.

Atherosclerosis

Example of endothelial dysfunction where chronic inflammation reduces endothelial adhesion, increasing permeability.

Cellular Mechanosensing

Normal function involves responding to mechanical cues to regulate behavior; disease can misregulate this function.

Pulmonary Fibrosis

Example where excessive collagen deposition stiffens lung ECM, leading to respiratory failure.

Cellular Metabolism

Normal function involves energy production through metabolic pathways; disease can lead to dysfunction.

Type 2 Diabetes

Example of beta-cell dysfunction due to chronic hyperglycemia impairing insulin secretion.

Mechanotransduction

Increased ECM stiffness disrupts glucose-stimulated insulin release.

Pathology

Systemic metabolic failure, hyperglycemia, organ damage.

Normal Function (Immune Cell Function)

The immune system defends against pathogens and removes damaged cells.

Disease Impact (Immune Cell Function)

Hyperactive or suppressed immune response drives pathology.

Example (Immune Cell Function)

Autoimmune Disease (Rheumatoid Arthritis)

Disruption (Immune Cell Function)

Overactive T cells and macrophages trigger chronic inflammation.

Mechanotransduction (Immune Cell Function)

Increased ECM degradation (MMPs) damages joints, worsening inflammation.

Pathology (Immune Cell Function)

Joint destruction, pain, loss of function.

Normal Function (Differentiation & Stem Cell Fate)

Stem cells differentiate into specialized cell types based on environmental signals.

Disease Impact (Differentiation & Stem Cell Fate)

Impaired differentiation disrupts tissue maintenance.

Example (Differentiation & Stem Cell Fate)

Osteoporosis (Bone Loss)

Disruption (Differentiation & Stem Cell Fate)

Aging and hormonal changes shift mesenchymal stem cells (MSCs) away from osteoblast differentiation.

Mechanotransduction (Differentiation & Stem Cell Fate)

Reduced ECM stiffness prevents MSCs from sensing mechanical cues needed for bone formation.

Pathology (Differentiation & Stem Cell Fate)

Weakened bones, fracture risk.

Proliferation

Rate at which cells divide and multiply.

Dysregulation of cell cycle

Altered signaling pathways (e.g., p53, Rb, Wnt).

Apoptosis

Programmed cell death.

Altered caspase activity

Mitochondrial dysfunction, loss of pro-apoptotic signaling (e.g., BAX, BCL-2).

Senescence

Irreversible cell cycle arrest with secretory phenotype (SASP).

Migration

Directed movement of cells.

Differentiation

Specialization of stem/progenitor cells.

Metabolism

Energy production and nutrient utilization.

ECM Remodeling

Degradation, deposition, or stiffening of the extracellular matrix.

Autophagy

Cellular self-digestion of damaged components.

Adhesion

Cell-cell and cell-ECM interactions.

Secretion

Release of cytokines, growth factors, or ECM components.

Chronic inflammation

excess pro-inflammatory cytokines

Cancer

paracrine signaling for tumor growth

Autoimmune diseases

hyperactive immune cell secretion

Endocytosis/Exocytosis

Cellular uptake or release of molecules

Clathrin-mediated endocytosis alterations

changes in endocytosis processes involving clathrin

Exosomal cargo changes

modifications in the contents of exosomes

Neurodegenerative diseases

defective synaptic vesicle cycling

Infectious diseases

pathogen entry

Extracellular Fluid

pH, Ion Balance, Nutrients

pH shifts

altered ion gradients, metabolic waste accumulation

Vascularization & Blood Flow

Abnormal angiogenesis, hypoxia, vascular leakage

Oxygen Tension

Altered oxygen availability, oxidative stress

Cell Presence & Activity

Chronic inflammation, immune suppression or hyperactivation

Lymphatic Drainage & Fluid Homeostasis

Impaired clearance of interstitial fluid, leading to swelling and toxin buildup

Metabolite Availability & Nutrient Competition

Depletion of key metabolites, competition between host cells and pathogens/tumor cells

Exosome & Extracellular Vesicle Dynamics

Increased or altered EV secretion, influencing signaling

Neuronal Signaling & Innervation

Changes in nerve density, neurotransmitter levels, and pain signaling

Hormonal & Endocrine Factors

Dysregulated hormone levels altering tissue responses

Epigenetic Landscape

Changes in DNA methylation and histone modifications affecting gene expression

Ocular Shingles

a viral infection affecting the eye and surrounding structures caused by the reactivation of the varicella-zoster virus (VZV)

Prevalence

the proportion of individuals who have a disease or condition at a specific point in time, including both new and existing cases

Incidence

the number of new cases of a disease that develop within a specific time period in a population at risk

Overall shingles incidence

~4 per 1,000 people per year

HZO incidence

~0.3 to 0.7 per 1,000 people per year

Recurrent Cases

About 10% of patients may experience recurrence

Sex-based differences

Slightly higher incidence in women, possibly due to differences in immune function

Prodromal phase

1-5 days before rash with pain, burning, tingling in affected dermatome

Acute eruptive phase

1-2 weeks with a red, blistering rash along the ophthalmic nerve distribution

Acute eruptive phase

1-2 weeks duration where a red, blistering rash appears along the ophthalmic nerve distribution.

Ocular involvement

Includes conjunctivitis, keratitis, uveitis, and scleritis.

Chronic/Postherpetic Phase

Weeks to months, or longer, characterized by persistent nerve pain known as postherpetic neuralgia (PHN).

Postherpetic neuralgia (PHN)

Persistent nerve pain that can last months to years.

Corneal scarring

Can lead to vision loss and secondary glaucoma in severe cases.

Neurotrophic keratopathy

Corneal desensitization leading to ulceration and perforation.