Cellular Adaptation To Stress

Cellular Adaption To Stress

Cellular adaptation refer to (usually) reversible changes in size, number, phenotype or appearance, metabolic activity or functions of cells in response to adverse environmental conditions or internal bodily stresses.

Basically, just as we react to something in our environment, cells don’t just sit there and take their punishment – they change to try to conquer the problem.

There are 4 important ways in which they do this:

  1. Hypertrophy
  2. Hyperplasia
  3. Atrophy
  4. Metaplasia

Hypertrophy and Hyperplasia

Hypertrophy is a cellular response that involves the increased size of cells, that results in an increase in size of the affected organ.


Note that there is no increase in the number of cells, rather JUST the size. This type of cellular adaptation to stress occurs in a number of different cells, and is usually coupled with another type of cellular adaptation, hyperplasia.

Hyperplasia is a cellular response that involves the increase in number of cells in response to a stimulus.


Both hyperplasia and hypertrophy occur as compensatory mechanisms to an increased workload on the organ or cell.

To remember which is which, think of the prefix and suffix that make up the word. The suffix “plasia” means “development” and thus hyperplasia means “increased development,” corresponding to an increase in the number of cells. Similarly, “-trophy” means “sustenance, nutrition” and thus, hypertrophy refers, in fact to the very mechanism of hypertrophy, an increase in factors that sustain and allow growth of the cells, which will be explained later.


If cells are divided into cells that are capable of dividing, and cells that are incapable of dividing, we can also divide the way they react to increased stress.

  1. Cells capable of dividing respond to an increased workload using both hyperplasia and hypertrophy.
  2. Cells incapable of dividing can only respond to an increased workload by hypertrophy. An example of this is in myocytes, or cardiac muscle cells in myocardial fibres. Thus, the heart mainly responds to an increased workload by hypertrophy. Other examples are adult skeletal muscles and neurons.

Physiologic vs Pathologic Hypertrophy and Hyperplasia:

Hypertrophy and hyperplasia, while it can be physiological to aid the body, may also be disease related, or pathological, and is a very important indicator of disease.

Physiologic Hypertrophy: is caused by an increased workload, increased functional demand or stimulation by hormones and growth factors. Of these, the most common stimulus for hypertrophy is increased workload. An example of workload induced hypertrophy would be the muscle enlargement in bodybuilders as muscles are forced to tolerate new loads. An example of hormone-induced hypertrophy is within the endometrium and myometrium of the uterus, as estrogen upregulation during the follicular stage of the menstrual cycle stimulates an increase in muscle proteins in the stroma of the endometrium and the large smooth muscle layer of the myometrium, and thus, muscle size.

Physiologic Hyperplasia: occurs most commonly due to the action of hormones or growth factors when there is a need to increase functional capacity of hormone sensitive organs, or when there is a need for functional compensatory increase after damage or resection of an organ. The most popular and easily understood examples of these would be the physiologic compensatory hyperplasia that occurs in the liver to restore the liver to normal size after an individual donates a lobe of the liver. Hormonal hyperplasia can be most easily illustrated in the breast, as cells within the breast proliferate greatly due to estrogen and progesterone at puberty and pregnancy.

Pathologic Hyperplasia: Caused mainly by an inappropriate or excessive action of hormones and growth factors acting on target cells. For example, benign prostatic hyperplasia (illustrated above) occurs due to excessive action of androgens such as dihydrotestosterone on testosterone receptors on the prostate gland. Alternatively, endometrial hyperplasia can also occur due to an imbalance between estrogen and progesterone, that causes an increase in the absolute or relative amount of estrogen, promoting an increase in cell proliferation in the endometrium, producing irregular menstrual bleeds. Usually, the hormonal stimulation can be regressed, HOWEVER, if the growth control mechanisms are also damaged, then cancer may result due to uncontrolled proliferation of cells. Thus, endometrial hyperplasia may eventually become endometrial cancer.  Thus, while hyperplasia is distinct from cancer, pathologic hyper­plasia constitutes a fertile soil in which cancerous proliferations may eventually arise. Hyperplasia is also a response to certain viral infections, such as HPV, that interfere with the ability of the cell to regulate cell proliferation.

Pathologic Hypertrophy: occurs in cardiac muscles when there is an increase in end-diastolic volume, or the amount of blood that must be pumped out of the heart per contraction that occurs due to faulty valves or hypertension. Similarly, if one kidney has a problem, then the opposite kidney increases its size to function at a higher efficiency to compensate for the opposite kidney (note the kidney cells also undergo hyperplasia).


Mechanism of Hyperplasia and Hypertrophy:


Hyperplasia is the result of growth factor driven proliferation of mature cells, and in some cases, by the increased output of new cells from tissue stem cells.

It occurs due to increased transcription factor production due to:

  • Increased production of Growth Factors
  • Increased levels of Growth Factor Receptors
  • Activation of intracellular signaling


Hypertrophy results from an increase in proliferation of cellular proteins. The increase in cellular proteins in cardiac myocytes in particular can occur due to several stimuli, such as mechanical stretch receptors which detect an increase workload, increase in growth factors and the presence of agonists. There are 3 basic steps in the synthesis of these cellular proteins:

  1. The integrated action of mechanical receptors, agonists and growth factors activates signal transduction pathways.
  2. These signal transduction pathways produce several transcription factors.
  3. These transcription factors in turn cause the increase in muscle protein synthesis and thus, hypertrophy.

It should also be noted that hypertrophy is indeed, also mediated by the conversion of adult form of contractile proteins, to the larger neonatal form of contractile proteins.


Atrophy refers to the decrease in the size of an organ or tissue due to a decrease in cell size and number.

Atrophy can also be either physiologic or pathologic.

Atrophy serves to decrease the nutrients required by the tissue/organ by decreasing metabolic demand, to still allow the cell to survive in pathologic cases; or simply to remove the cell in physiologic cases.

Physiologic Atrophy:

Physiologic Atrophy is actually very common in the transition to the fetal body to the adult body. The body asks itself, “What do I not need anymore?” and gets rid of it so as to divert nutrients to more important locations.

Physiologic atrophy occurs most evidently in the thymus gland and the thyroglossal duct.


Notice how much smaller the thymus gland is in the adult when compared to the fetus! The thymus gland is responsible for the maturation of T-lymphocytes, and thus, once they have matured, the thymus plays no significant function, and it atrophies.

Similarly, the thyroglossal duct produces the thyroid gland via a long duct, and since only the distal part or the lower part of the duct forms the gland, the proximal part is unnecessary and is removed by atrophy.

There may also be physiologic atrophy in adult life, and this occurs in the uterus just after giving birth. This is because the uterus was enlarged so as to allow sufficient contractile force from the endometrium to push the baby out of the womb, and also enlarged to house the developing fetus. After birth, this is no longer required, and portions of the uterus atrophy.

Pathologic Atrophy:


Pathologic atrophy has several causes:

  • Disuse: Disuse atrophy occurs when there is a decrease in the use of a particular organ or muscle. This can occur pathologically by conditions that prevent use of the particular organ or muscle. For example, if a particular individual is immobilized by fracturing a bone, and must be restricted to complete bed rest, he cannot use the muscle, and the body decides to decrease the size of the cell so as to divert nutrients elsewhere. Usually, this is reversible once usage restarts. Disuse atrophy also occurs in poliomyelitis, as muscle weakness in the disease will eventually prevent movement, and the muscle atrophies.
  • Denervation: When denervation occurs, muscle cells receive no nervous signals, and also lose trophic factors from nerves that promote growth, resulting in atrophy.
  • Ischemia: Gradual decrease in blood supply to the tissue due to gradual occlusion of the artery supplying the tissue causes a decreased delivery of nutrients to the tissue, and atrophy occurs. A phenomenon known as senile atrophy occurs in very elderly who also have atherosclerosis, where the brain receives fewer nutrients and atrophies, aiding in dementia.
  • Inadequate Nutrition: Nutrient deficiencies such as protein malnutrition or marasmus will eventually result in the muscle proteins being used as a source of energy, causing severe muscle atrophy, called cachexia. This type of atrophy also occurs when diseases that affect the appetite occur, as fewer nutrients are consumed and regions of the body, especially muscle, atrophies.
  • Loss Of Endocrine Stimulation: Some tissues in the body grow in response to hormones, such as the breast, which grows in response to estrogen and progesterone stimulation. If these hormones are lost, or the endocrine system does not stimulate the body organs, these regions atrophy.
  • Aging
  • Pressure: Tissue compression results in the tissue undergoing atrophy to decrease size so as to fit comfortably in its original space. This occurs very commonly in the growth of tumors, that grow and suppress surrounding, normal tissues. The mechanism is believed to be the compression of surrounding blood capillaries that supply surrounding tissues, and thus may also be classified as an ischemic atrophy.

Mechanism of Atrophy:

Atrophy results primarily from decreased protein synthesis due to decreased metabolic activity, and increased proteolysis in cells. This proteolysis occurs via 2 mechanisms:

  1. Ubiquitin-proteasome pathway: Nutrient deficiencies activiate ubiquitin ligases, which attach the protein, ubiquitin to cellular proteins. Ubiquitin serves as a cellular target, and marks the entire ubiquitin-protein complex for breakdown via proteasome activity. [Most important mechanism]
  2. Autophagy: Increased autophagic vacuole formation occurs as the cell rapidly degrades or eats its own components so as to decrease nutrient demand to match the nutrient supply. Some residue from autophagy is called lipofuscin granules, a brown pigment that builds up as autophagy increases – causing tissues undergoing this type of atrophy to appear brown. This type of atrophy is called brown atrophy.


Metaplasia is a reversible change where one differentiated cell type (epithelial or mesenchymal) is replaced by another cell type.

It occurs when a cell that is unable to withstand stress is replaced by another cell type that is better able to handle and deal with the stress. It’s like Captain America having to assembling the Avengers to deal with massive threats, because he isn’t able to deal with it alone, although he can deal with smaller, street-level threats by himself.

The best example of an epithelial metaplasia is a change from ciliated columnar type cells to stratified squamous type cells in the respiratory tract in response to chronic irritation, the most important example of which is smoking.


In the diagram above, clearly visible is the gradual conversion of the normal mucus producing, ciliated columnar cells to a more rugged stratified squamous layer of cells, which is better able to survive against the harsh chemicals within cigarette smoke. A conversion of columnar cells to squamous stratified cells also occur in the ducts of the salivary glands and pancreas, or bile duct in the presence of damaging stones. In both these cases, the more rugged stratified squamous cells allow the survival of the cell in its harsh environment. in addition, a Vitamin A deficiency can also cause the conversion of columnar cells to squamous cells in respiratory epithelium, for a reason you will see below.

The disadvantage of this, however, is the intended effect of the original cell type is now lost. For example, in the respiratory epithelium, the columnar cells which usually produce mucus and protect from infection via cilia are now absent, and it is easer for the lung to become infected. Thus, metaplasia must be reversed whenever possible. If the irritation is prolonged however, then malignant metaplasia may occur, which may eventually result in cancer.

It should be noted that squamous to columnar changes also occur, as in Barret’s Esophagus due to gastric reflux, which mucus producing columnar cells survive better.


Connective tissue metaplasias may also occur, where mesenchymal cells such as osteocytes, adipocytes and fibroblasts form in irregular areas such as within muscle. These usually are pathological and irregular, occurring not as an adaptive change, but directly due to cell and tissue injury.

Mechanism of Metaplasia: 

Metaplasia occurs due to the actual reprogramming of stem cells that exist in normal tissues, or undifferentiated mesenchymal cells present in connective tissue. Stem cells are found in the epithelia and the embryonic mesenchyme.

Thus, these precursor cells actually differentiate across a new pathway, that generates a different type of cell entirely. This differentiation is mediated by signals from cytokines, growth factors and extracellular matrix components in the cell’s vicinity. These stimuli all serve as stimuli that direct the cells towards a specific differentiation pathway.

Of special note is Vitamin A, or retinoic acid. Vitamin A controls gene transcription directly by directly acting on nuclear retinoid receptors, affecting the direction of cell differentiation. Thus, either a vitamin A absence or excess can cause metaplasia, as in the metaplasia of respiratory tract in Vitamin A absence.

There is also one additional phenomenon that must be mentioned, called dysplasia.


Dysplasia refers to abnormal changes in cellular shape, size and organization. Dysplasia is a term that literally means, “disorganized growth.”

It is very commonly referred to as abnormal hyperplasia, in which a large number of cells, usually immature, are rapidly produced, but in a terribly disorganized fashion, of the wrong cell type and of random sizes. Obviously then, it is not physiologic, and is in fact pathologic.


There is therefore an irreversible increase in the production of immature cell types, and a decrease in production of mature cells. It can therefore be contrasted with metaplasia since metaplasia is the reversible replacement of mature cells with another mature cell type, while dysplasia produces random, immature cell types, an irreversible change.

Consequently, dysplasia is described as a preneoplastic lesion, indicative of the first stage of malignant cancer. Eventually, dysplasia causes such a large amount of uncontrolled cell division that a tumor forms, called carcinoma in situ that rests on the basement membrane. If allowed to penetrate the basement membrane, it becomes malignant cancer, capable of metastasizing.


There are 4 principal features of dysplasia:

  1. Anisocytosis: cells of unequal size
  2. Poikilocytosis: abnormally shaped cells
  3. Hyperchromatism: excessive pigmentation
  4. Presence of am abnormally large amount of mitotic figures, indicative of a large number of dividing cells.

That’s all guys!

Here are a couple extra resources:


Pathophysiology of Cellular Adaptation (20:36 seconds)

One Minute Medical School (1:00 Quick Review)

Cellular Adaptations by Dr. Rabiul Haque (From 13:18 onwards)


1. A 51-year-old male has a blood pressure of 150/95mmHg. If this persists for years, which of the following will be the appropriate compensatory response in the heart?

A. Hyperplasia

B. Dysplasia

C. Hypertrophy

D. Metaplasia

E. Atrophy

2. After several weeks of immobilization, you can expect the following change to occur to the calf muscle.

A. Hyperplasia

B. Dysplasia

C. Hypertrophy

D. Metaplasia

E. Atrophy

3. A 32 year old male experiences “heartburn” with substernal pain from reflux of gastric contents into the lower esophagus. After many months, which of the following histological changes would you expect?

A. Squamous metaplasia

B. Mucosal hypertrophy

C. Columnar epithelial metaplasia

D. Atrophy of lamina propria of basement membrane

E. Goblet Cell hyperplasia

4. Accumulation of lipofuscin granules is commonly seen in which of the following conditions?

A. Metaplasia

B. Hypertrophy

C. Atrophy

D. Hyperplasia

E. Dysplasia

5. The non pregnant uterus of a 20 year old female nurse measured 7cm x 4cm x 3cm. Just before giving birth, it was found to measure 34cm x 18cm x 12cm. Which of the following could be the main reason for this?

A. Endometrial glandular hyperplasia

B. Myometrial fibroblast proliferation

C. Endometrial stromal hypertrophy

D. Myometrial smooth muscle hypertrophy

E. Vascular endothelial hyperplasia

Answers: C, E, C, C, D

[Why D, and not C for number 5? While both D and C are correct, the endometrium is only a small lining, and contributes only minimally to the increase in size of the uterus when compared to the myometrial smooth muscle hypertrophy.]

Hope this helps!

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