Cell Death: Apoptosis and Necrosis
- NanoEntek
- Jul 3, 2025
- 5 min read
Updated: Jan 6
Why Is Cell Death Necessary?
In multicellular organisms, tissues are continuously renewed. Old, damaged, or unnecessary cells must be removed to allow functional cells to take their place.
For example, the human body sheds approximately 30,000–40,000 skin cells per hour, maintaining skin integrity and resilience.
What Happens When Cell Death Fails?
When cells fail to die appropriately, several pathological outcomes may occur. This dynamic balance between cell death and cell regeneration is fundamental to maintaining tissue health and overall physiological stability. Disruption of the balance between cell death and cell growth can lead to cancer, aging, and developmental abnormalities.
1. Cancer
If damaged or mutated cells escape programmed cell death, they can proliferate uncontrollably and form tumors.
When damaged or mutated cells escape programmed cell death and continue to divide unchecked, they can accumulate and form tumors. This uncontrolled growth is one of the hallmarks of cancer. The failure to eliminate these harmful cells allows them to proliferate and invade other tissues.
2. Impaired Tissue Renewal
Persistent old or damaged cells reduce regenerative capacity, accelerating aging and organ dysfunction. If old or damaged cells persist without being replaced, tissues lose their ability to repair and regenerate. This can accelerate aging and lead to a decline in organ function over time. The inability to form new, healthy cells can also compromise the body’s natural healing processes.
3. Developmental Abnormalities
During embryonic development, excess cells must be selectively removed to shape tissues. Thus, cell death is critical during embryonic development because it helps shape structures by removing excess cells in a tightly regulated manner. For instance, without proper cell death during fetal development, malformations such as webbed fingers or toes (a condition known as syndactyly) can occur due to the failure to separate individual digits.
What Are the Two Major Types of Cell Death?
Broadly, cell death is classified into programmed (apoptosis) cell death and unprogrammed (necrosis) cell death. Apoptosis is a regulated, non-inflammatory form of cell death, while necrosis is uncontrolled and pro-inflammatory. At its essence, cell death marks the conclusion of a cell’s life cycle—a natural and universal event that occurs for various reasons throughout an organism’s lifespan. Some cells are programmed to die during early development and never reach full maturity. Others reach the end of their replicative capacity and naturally shut down. Additionally, cells that incur irreparable damage are actively removed to maintain tissue health and prevent further harm.
Beyond these intrinsic processes, external factors such as infections, physical injuries, toxic substances, or even certain medical treatments can also induce cell death by damaging the cell’s structure or disrupting its internal machinery.
Programmed cell death is a tightly controlled biological process that serves the organism’s long-term benefit. Sometimes referred to as “cellular suicide,” it involves an internal signaling cascade that leads to the cell’s systematic dismantling without causing inflammation. Common types include apoptosis and autophagy.
In contrast, unprogrammed cell death, most notably necrosis, is a sudden and uncontrolled response to severe external damage. This type of cell death often results in cell rupture and triggers inflammatory responses, which can lead to further tissue injury.
Understanding the difference between these two forms of cell death—internally initiated and externally induced—is crucial, as each involves distinct molecular pathways and has very different biological consequences. Distinguishing apoptosis from necrosis is critical for accurate interpretation of experimental and therapeutic outcomes.
Programmed Cell Death: Apoptosis
Apoptosis is a tightly regulated process that eliminates unwanted or damaged cells without provoking inflammation.
Key characteristics of apoptosis
Cell shrinkage
Chromatin condensation
DNA fragmentation
Formation of membrane-bound apoptotic bodies
Apoptotic pathways
1. Intrinsic Pathway (Mitochondrial Pathway)
Triggered by internal stress such as DNA damage or oxidative stress.
Mitochondria release cytochrome c, activating caspases that dismantle the cell
2. Extrinsic Pathway (Death Receptor Pathway)
Initiated by extracellular ligands (e.g., FasL, TNF-α) binding to death receptors, also leading to caspase activation.
After birth, this process continues to support tissue homeostasis, playing a crucial role in:
Replacing aging or damaged cells
Supporting the immune system by eliminating infected or malfunctioning cells
Preventing the proliferation of cells with irreparable damage (such as potential cancer cells)
Unprogrammed Cell Death: Necrosis
In contrast to apoptosis, necrosis is an uncontrolled response to severe external damage such as trauma, toxins, or ischemia.
Key characteristics of apoptosis
Cell swelling
Early membrane rupture
Leakage of intracellular contents
Strong inflammatory response
Because necrosis lacks the regulation seen in programmed cell death, it often results in collateral damage, exacerbating tissue dysfunction and disease progression.
Cells that die of necrosis display one of the six characteristics below [4].
Coagulative necrosis | caused by a lack of blood supply and cell structure remains |
Liquefactive necrosis | caused by infection and lack of oxygen but cell structure is disrupted and becomes liquified |
Fat necrosis | a death of fat tissue caused by injury |
Caseous necrosis | a cellular death that occurs in tissue |
Fibrinoid necrosis | a cellular death caused by blood vessel damage |
Gangrenous necrosis | a death of tissue caused by a lack of blood supply |
Apoptosis vs. Necrosis: Decision-Level Comparison
The distinctions between apoptosis and necrosis are profound, shaping their physiological roles and pathological implications. While both lead to cell death, their mechanisms, triggers, and consequences are fundamentally different. The table below provides the difference between these two critical processes:
Feature | Apoptosis | Necrosis |
Nature | Programmed, active, regulated, "cellular suicide" | Unprogrammed, accidental, passive, uncontrolled |
Triggers | Intrinsic signals (DNA damage, stress), extrinsic signals (death ligands), developmental cues, lack of survival factors | External factors (trauma, infection, toxins, ischemia, extreme physical/chemical insult) |
Cell Size | Shrinks | Swells |
Plasma Membrane | Intact, forms blebs, phosphatidylserine (PS) externalization | Ruptures early, loss of integrity |
Organelles | Remain intact, may condense | Swell, rupture |
Nucleus | Fragmentation, chromatin condensation, DNA laddering | Swelling, less organized DNA fragmentation, lysis |
Cellular Contents | Packaged into apoptotic bodies, no leakage | Leaked into extracellular space |
Inflammatory Response | Immunologically silent, anti-inflammatory, efficient phagocytic clearance | Pro-inflammatory, triggers immune response via DAMPs |
Physiological Role | Beneficial (development, tissue homeostasis, removal of damaged cells) | Pathological (causes tissue damage, disease) |
How Can Apoptosis and Necrosis Be Distinguished Experimentally?
Understanding how and why cells die is fundamental in biomedical research—particularly in developing effective cancer therapies. Among various forms of cell death, apoptosis (programmed cell death) and necrosis (uncontrolled cell death) are two primary types. Accurately distinguishing between these processes is essential, as they have very different biological implications and responses to treatment. This is where advanced analytical tools, such as cell analyzers, come into play.
One of the most widely used techniques for studying apoptosis and necrosis is flow cytometry or similar image-based cytometric analysis. Instruments like NanoEntek’s ADAMII LS are designed to differentiate these types of cell death based on changes in cell membrane structure. In healthy cells, the membrane is tightly closed by a lipid bilayer, composed of hydrophilic (water-attracting) heads and hydrophobic (water-repelling) tails. One of the key molecules in this bilayer is phosphatidylserine (PS), which is normally located on the inner side of the membrane.
Early Apoptosis
During early apoptosis, PS flips from the inner to the outer surface of the membrane—a process known as "PS externalization." This flipping can be detected using Annexin V conjugated with FITC (a green fluorescent dye), which binds specifically to externalized PS. At this stage, the membrane remains intact, allowing FITC-Annexin V binding without permitting other stains to enter the cell.
Late Apoptosis
As apoptosis progresses, the cell membrane begins to lose its integrity. This allows DAPI, a fluorescent stain, to enter the cell and bind to the nucleus. When both FITC (Annexin V) and DAPI signals are detected, the cell is identified as being in late apoptosis.
Necrosis
Unlike apoptosis, necrotic cells do not exhibit PS flipping. However, their membranes are also compromised—often severely—allowing DAPI to enter. In necrotic cells, only DAPI is detected, without any FITC signal.
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