Lecture 1: Growth of cells and tissues
Regenerative medicine aims to cure and complete functional recovery, allows for growth and
adaptation. RM is a multidisciplinary field e.g. molecular biology, disease mechanisms and
biomechanics are required.
Concise recapitulation
The basic principle of tissue engineering →
Cell mechanics
- Mechanical properties and internal forces
- Cell deformation
- Cell environment
- Dictated by cell composition and organization
Mechanotransduction
- Metabolism
- Biochemical signals
- Secretion
- Growth/ movement
- Gene expression
- Cell-cell and cell-matrix interaction
Cell membrane = viscous membrane; double layer of phospholipids including proteins,
carbohydrates and cholesterol. Very flexible and it does allow active and passive transport
Cytoplasm = gel-like, visco-elastic material containing cytosol, organelles, vesicles and
cytoskeleton
Cytoskeleton = made out of actin, intermediate filaments and microtubules. Important for:
cell motility, transport, contraction, signal transduction, reproduction, airway-clearance,
gastro-intestinal absorption, hearing and water-absorption in nephron
- Cell division, migration and transport requires dynamic filaments and molecular
motors
Actin microfilaments can form compact fiber bundles or loose networks, and play a role in
cell contraction, movement, transport and the cell phenotype. These are linked to ECM via
integrins (focal adhesion points).
Formation of “stress fibers” (crosslinked filament bundles with myosin II motors) →
necessary for cell adhesion to substrate, contractile tension and changes in cell shape
Intermediate filaments provide tensile strength to the cell – rigid and stable elements.
Microtubules determine cell shape and distribution of organelles, movement and transport.
Cell-cell & cell-matrix interaction → coupling chemistry and physics. Output parameters e.g.
adhesion probability,- rate,- strength and - lifetime
Niche = cellular micro-environment
The cell controls its matrix and the matrix controls the cell; reciprocity
ECM = fibrillary components (collagen, elastin, GAGs), relevant for structure and function,
adaption, remodeling
,Number of cells in adult human body = 6E13 – 1E14
Triggers for growth and proliferation
- Based on ‘supply and demand’ – to reach homeostasis
- Physical limitations: ratio cell size/ nuclear size
- Stimuli orginate in cytoplasm (intrinsic)
- Stimuli form extracellular environment (‘molecular signaling’ and ‘mechanical cues’)
Cell growth and division – diversity
- Not all cells divide and grow at the same time and rate
- Growth is controlled
- Internal programming → telomerase
- Hormones and nerves
Tissue growth and homeostasis occurs either via stem cell division or normal cell division
➔ Stem cell can renew itself indefinitely and upon division can turn into another cell
type
➔ Low division rate (‘turnover’)
Homeostasis is the balance between synthesis and degradation. Depends on ‘wear & tear’,
ongoing proliferation of cells or tissue specific stem cells (=maintenance). In case of damage
(= tissue repair)
Senescence = the reduced maintenance potential, losses will not be made up for, reduced
homeostasis. More degradation than synthesis.
Lecture 2: Processes and control of growth
I. Embryonic growth – massive proliferation and
differentiation and organization (production of
matrix)
II. Postnatal growth – proliferation, differentiation.
The growth is often tissue specific, some tissues
increase more than others.
III. Homeostasis – maintenance, cells are
constantly dying and need to be replaced. So in this phase it is important to find the
balance. Tissue turnover and injury
IV. Ageing – the tissues lose their regenerative capacity. Which leads to a decrease of
cell mass, changes in the extracellular matrix. E.g. the changes you see in skin
during ageing (collagen production decreases)
Cells are the binding blocks of tissues. Embryonic growth starts with the fertilized egg cell.
,Adult stem cells are the building blocks for postnatal growth/ homeostasis. Organ specific
stem cells, these are of high interest for regenerative medicine, mostly bone marrow, blood
or fat derived stem cells. Because these are easy to isolate, propagate and have a high
regenerative potential.
➔ Induced pluripotent stem cells – already differentiated however they can be
redifferentiated into any stem cell.
Niches → physical and physiological space, interplay between the niche and the rest of the
body balances the function of stem cells to the need of the organisms. Adult stem cells can
be found in niches.
- Specific location
- Supporting cells are present
- Specific chemical environment, requiting factors (growth factors, hormones, calcium
etc.)
- Specific mechanical environment, e.g. the ECM has a specific stiffness or elasticity
Satellite cell: stem cell of the muscle
Tissue renewal (turnover) and regeneration
• The ability of most tissues to maintain homeostasis and to repair injury is linked to
stem cells
• In many cases cells lose their ability to proliferate when they differentiate
• Differentiated cells can contribute to growth by synthesis of matrix
• Limited capacity for cell growth (energetically not favorable, membrane to cytoplasm
ratio)
Tissue regeneration/development through stem cells
- Ability of tissue to regenerate/ maintain homeostasis is linked to stem cells
- The number of stem cells and their genetic integrity needs to be controlled
- Depletion of stem cell pool→ loss of regenerative potential
- Mutations in stem cells → cancer
Summary
• Growth: cells and extracellular matrix
• Tissue architecture (organization of cells and matrix) is important for function
• Growth: Balance between proliferation, death and senescence
Balance between ECM production, degradation and organization
• Embryonic stem cells and adult stem cells/different potency and specific niches
• Stem cells of interest in regenerative medicine
Control of tissue growth through regulation of cell proliferation
• Extrinsic and intrinsic factors
• Availability of nutrients
• Signals from other cells
• Other signals from the niche (mechanical cues, oxygen, hormones growth factors)
• Cell cycle control mechanisms
• Cell aging
, ➔ Some cells grow dramatically in size after cell cycle withdrawal (muscle cells and
nerves)
mTOR pathway → major regulator of cell growth. Artificial activation can promote
proliferation in almost all cell types (e.g. glucose, transmitters, amino acids). mTORC
integrates inputs from at least four other major cues that affect cell growth and proliferation:
stress, energy status, oxygen, and amino acid level
Hippo signaling pathway is an evolutionarily conserved mediator of growth control, cell fate
decisions and stem cell identity. It is a protein kinase (MST1/2 in human). Mutations leads to
overgrowth. Regulated by tissue architecture and mechanics. Hippo is a negative regulator
of YAP and TAZ.
Regulation of cell division
- How many times can a cell divide (hayflick number / telomers)
- Check points and check point regulators in the cell cyclus
- Sensors of damage and unfavorable conditions
- Cell cycle arrest or death (often tumor suppressors ex. P53, Rb)
Summary human stem cells (HSC)
• Growth depends on cells ability to proliferate and grow
• Growth and proliferation is regulated by control proteins which integrates the signals
from the environment with the state of the cell
- Proliferation and growth is regulated by both cell internal and external
signals
- The signals are regulated by nutrients, stress, mechanics, architecture
- Complex feedback and crosstalk between the pathways allows for tight
control of proliferation and growth
• The phase of the life time and aging of the cell influences the cells ability to
proliferate.
Regenerative medicine aims to cure and complete functional recovery, allows for growth and
adaptation. RM is a multidisciplinary field e.g. molecular biology, disease mechanisms and
biomechanics are required.
Concise recapitulation
The basic principle of tissue engineering →
Cell mechanics
- Mechanical properties and internal forces
- Cell deformation
- Cell environment
- Dictated by cell composition and organization
Mechanotransduction
- Metabolism
- Biochemical signals
- Secretion
- Growth/ movement
- Gene expression
- Cell-cell and cell-matrix interaction
Cell membrane = viscous membrane; double layer of phospholipids including proteins,
carbohydrates and cholesterol. Very flexible and it does allow active and passive transport
Cytoplasm = gel-like, visco-elastic material containing cytosol, organelles, vesicles and
cytoskeleton
Cytoskeleton = made out of actin, intermediate filaments and microtubules. Important for:
cell motility, transport, contraction, signal transduction, reproduction, airway-clearance,
gastro-intestinal absorption, hearing and water-absorption in nephron
- Cell division, migration and transport requires dynamic filaments and molecular
motors
Actin microfilaments can form compact fiber bundles or loose networks, and play a role in
cell contraction, movement, transport and the cell phenotype. These are linked to ECM via
integrins (focal adhesion points).
Formation of “stress fibers” (crosslinked filament bundles with myosin II motors) →
necessary for cell adhesion to substrate, contractile tension and changes in cell shape
Intermediate filaments provide tensile strength to the cell – rigid and stable elements.
Microtubules determine cell shape and distribution of organelles, movement and transport.
Cell-cell & cell-matrix interaction → coupling chemistry and physics. Output parameters e.g.
adhesion probability,- rate,- strength and - lifetime
Niche = cellular micro-environment
The cell controls its matrix and the matrix controls the cell; reciprocity
ECM = fibrillary components (collagen, elastin, GAGs), relevant for structure and function,
adaption, remodeling
,Number of cells in adult human body = 6E13 – 1E14
Triggers for growth and proliferation
- Based on ‘supply and demand’ – to reach homeostasis
- Physical limitations: ratio cell size/ nuclear size
- Stimuli orginate in cytoplasm (intrinsic)
- Stimuli form extracellular environment (‘molecular signaling’ and ‘mechanical cues’)
Cell growth and division – diversity
- Not all cells divide and grow at the same time and rate
- Growth is controlled
- Internal programming → telomerase
- Hormones and nerves
Tissue growth and homeostasis occurs either via stem cell division or normal cell division
➔ Stem cell can renew itself indefinitely and upon division can turn into another cell
type
➔ Low division rate (‘turnover’)
Homeostasis is the balance between synthesis and degradation. Depends on ‘wear & tear’,
ongoing proliferation of cells or tissue specific stem cells (=maintenance). In case of damage
(= tissue repair)
Senescence = the reduced maintenance potential, losses will not be made up for, reduced
homeostasis. More degradation than synthesis.
Lecture 2: Processes and control of growth
I. Embryonic growth – massive proliferation and
differentiation and organization (production of
matrix)
II. Postnatal growth – proliferation, differentiation.
The growth is often tissue specific, some tissues
increase more than others.
III. Homeostasis – maintenance, cells are
constantly dying and need to be replaced. So in this phase it is important to find the
balance. Tissue turnover and injury
IV. Ageing – the tissues lose their regenerative capacity. Which leads to a decrease of
cell mass, changes in the extracellular matrix. E.g. the changes you see in skin
during ageing (collagen production decreases)
Cells are the binding blocks of tissues. Embryonic growth starts with the fertilized egg cell.
,Adult stem cells are the building blocks for postnatal growth/ homeostasis. Organ specific
stem cells, these are of high interest for regenerative medicine, mostly bone marrow, blood
or fat derived stem cells. Because these are easy to isolate, propagate and have a high
regenerative potential.
➔ Induced pluripotent stem cells – already differentiated however they can be
redifferentiated into any stem cell.
Niches → physical and physiological space, interplay between the niche and the rest of the
body balances the function of stem cells to the need of the organisms. Adult stem cells can
be found in niches.
- Specific location
- Supporting cells are present
- Specific chemical environment, requiting factors (growth factors, hormones, calcium
etc.)
- Specific mechanical environment, e.g. the ECM has a specific stiffness or elasticity
Satellite cell: stem cell of the muscle
Tissue renewal (turnover) and regeneration
• The ability of most tissues to maintain homeostasis and to repair injury is linked to
stem cells
• In many cases cells lose their ability to proliferate when they differentiate
• Differentiated cells can contribute to growth by synthesis of matrix
• Limited capacity for cell growth (energetically not favorable, membrane to cytoplasm
ratio)
Tissue regeneration/development through stem cells
- Ability of tissue to regenerate/ maintain homeostasis is linked to stem cells
- The number of stem cells and their genetic integrity needs to be controlled
- Depletion of stem cell pool→ loss of regenerative potential
- Mutations in stem cells → cancer
Summary
• Growth: cells and extracellular matrix
• Tissue architecture (organization of cells and matrix) is important for function
• Growth: Balance between proliferation, death and senescence
Balance between ECM production, degradation and organization
• Embryonic stem cells and adult stem cells/different potency and specific niches
• Stem cells of interest in regenerative medicine
Control of tissue growth through regulation of cell proliferation
• Extrinsic and intrinsic factors
• Availability of nutrients
• Signals from other cells
• Other signals from the niche (mechanical cues, oxygen, hormones growth factors)
• Cell cycle control mechanisms
• Cell aging
, ➔ Some cells grow dramatically in size after cell cycle withdrawal (muscle cells and
nerves)
mTOR pathway → major regulator of cell growth. Artificial activation can promote
proliferation in almost all cell types (e.g. glucose, transmitters, amino acids). mTORC
integrates inputs from at least four other major cues that affect cell growth and proliferation:
stress, energy status, oxygen, and amino acid level
Hippo signaling pathway is an evolutionarily conserved mediator of growth control, cell fate
decisions and stem cell identity. It is a protein kinase (MST1/2 in human). Mutations leads to
overgrowth. Regulated by tissue architecture and mechanics. Hippo is a negative regulator
of YAP and TAZ.
Regulation of cell division
- How many times can a cell divide (hayflick number / telomers)
- Check points and check point regulators in the cell cyclus
- Sensors of damage and unfavorable conditions
- Cell cycle arrest or death (often tumor suppressors ex. P53, Rb)
Summary human stem cells (HSC)
• Growth depends on cells ability to proliferate and grow
• Growth and proliferation is regulated by control proteins which integrates the signals
from the environment with the state of the cell
- Proliferation and growth is regulated by both cell internal and external
signals
- The signals are regulated by nutrients, stress, mechanics, architecture
- Complex feedback and crosstalk between the pathways allows for tight
control of proliferation and growth
• The phase of the life time and aging of the cell influences the cells ability to
proliferate.
