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Summary Regenerative Medicine (WBBE015) for second year biomedical science and biomedical engineering students at the RUG
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All content of the lectures summarized for the course regenerative medicine.
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Regenerative medicine1-2-2021
Lecture 1
Regenerative medicine: cells, scaffold, molecules. It is all about cell types, cell sourcing etc. The
engineering of this can be marketed. It is the branch of medicine that develops methods to regrow,
repair or replace damaged or diseased cells, organs or tissues.
Treating loss of organ function:
- Transplantation. However, it can be rejected and there are not enough donors.
- Implantation of prosthetic device.
- Autografting.
- Stem cells.
- In vivo induction of regeneration. Taking cells of the patient and regenerate the needed
tissue, organ etc. and transplanting it back → engineering an organ.
A problem of regenerative medicine with an implant is the response of the body to the foreign
material.
BBB principle: from bed to bench and Back. Patient with problem on the bed → go the lab and find a
solution (bench) → therapy and apply it to the patient (give the design back to those who need it).
Acute damage
• Bone fracture
• Cut skin
• Myocardial infarction
Chronic damage
• Non-healing wounds
• Hypertrophic scars
• Fibrosis
• Diabetes: hyperglycemia
• Smoking: CO, tar
• Obesity: hyperlipidemia
Regenerative medicine: damage → repair → regeneration
A part of repair and regeneration is wound healing → rebuilding → training / maturation.
What makes a tissue?
Tissue is like a compute network.
- All cells need to communicate with each other. It receives and gives information to
neighboring cells. Communication is key for a tissue. You get input and output from the cells.
This communication is needed for the homeostasis in
a tissue.
- Need a helping hand when something goes wrong.
When the homeostasis is disturbed, the tissue needs
help to repair / regenerate.
Pillars of tissue (homeostasis): communication
Basically, when there is damage, it needs to be repaired /
regenerated (wound healing). In regenerative medicine, they
first try to augment existing processes or re-educate the
microenvironment. When the case worse, it needs tissue
engineering, so making a replacement tissue. In the image on
the right, all fields and aspects of regeneration are visualized.
,Regeneration occurs in lower organisms. For example, in other animals when a limb is amputated it is
able to grow back.
Development, patterning & molecules signaling: molecules
- Regulatory molecules provide instructive signals for proliferation, differentiation and
function.
- Adherence molecules provide support/tethering, instructive signaling and sequestration of
regulatory molecules.
Regeneration = the ability of an organism, organ or tissue to regain its original structure and function
after damage.
Tissue engineering = an interdisciplinary field that applies the principles of engineering and the life
sciences toward the development of biological substitutes that restore, maintain or improve tissue
function.
The aim and targets of regenerative medicine is to devise new therapies for patients with severe
injuries or chronic diseases in which the body’s own responses do not suffice to restore functional
tissue.
What is needed to make a tissue?
You can compare it to building a house:
- Scaffold → matrix
- Bricks → (stem) cells
- Mortar (cement) → adhesion molecules
- Builder → Growth factors
RM trinity: cells + scaffolds + molecules. All components are
needed in order to apply regenerative medicine / tissue
engineering.
Choice of cells
Autologous = cells from the patient.
Allogenic = cells from another donor.
Types of cell cull culture:
- Mono layer (adherent cells)
- Suspension (non-adherent cells)
- Three-dimensional (scaffolds or templates)
Autologous cells:
- Can be stem/progenitor or somatic cells.
- Are obtained from the patient.
- Are isolated from small biopsies or blood.
- Can be best used for permanent structure repair.
o Pro’s → no rejection / fit patient
o Con’s → may be affected by disease (the stem cells are sometimes affected by an
autoimmune disease e.g.), small numbers can be taken, require individualized
culture (expensive) and are not available off-the-shelf.
Allogeneic cells:
- Can be stem / progenitor cells.
- Are obtained from various tissues: blood, bone marrow, fat, amniotic fluid, cord blood, ESC.
- Best used for temporary restoration/repair.
o Pro’s → can be obtained and cultured in large numbers, bulk culture (so uniform cell
batches and thus less expensive), cell banking possible and off-the-shelf availability.
With one batch of cells many patients with many conditions can be helped.
o Con’s → rejection, so immune suppression may be necessary.
,Immune compatibility is the ideal scenario, in which a bioengineered construct is accepted without
the need of immune suppression. Otherwise if this cannot be the case:
- Use immune privileged cells, like embryonic stem cells. These express low levels of MHC I
and no MHC II.
- Cell banking allow histocompatibility matching.
- Use cells with immunoregulatory function, like mesenchymal stem cells, which induce
tolerance in grafts.
Stem cells
They unspecialized, can self-renew and can differentiate into various functional phenotypes
depending the signals given to it (depending on the environment).
- Totipotent stem cell: these cells have unlimited capability and have the ability to form
extraembryonic membrane and tissues, the embryo itself, and all postembryonic tissues and
organs. An example is an embryo.
o They can form all the cell types in a body + extraembryonic or placental cells.
Embryonic cells within the first couple of cell divisions after fertilization are the only
cells that are totipotent.
- Pluripotent stem cell: these cells are capable of giving rise to most, but not all, tissue of an
organism. An example is inner mass cells.
o Can give rise to all of the cell types that make up the body. Embryonic stem cells are
considered pluripotent.
- Multipotent stem cell: these cells are committed to give rise to cells that have specific
function. An example is blood stem cells.
o Can develop into more than one cell type, but are more limited than pluripotent
cells. Adult stem cells and cord blood stem cells are considered multipotent.
Embryonic stem cells are derived from the inner cell mass of early embryos. The advantages is that
they have unlimited self-renewal. They do not yet have a commitment to give rise to a cell that has a
specific function (multipotency). Disadvantages on the other hand are the genomic instability and
that they are tumorigenic (they form teratomas). Besides that, there are also ethical issues. The
challenge with embryonic stem cells is to direct the multi-step differentiation to the desired cell type.
Multipotency must be controlled.
Adult stem cells are derived from various sources/organs. Everybody has their own stem cells →
mesenchymal stem cells; organ specific stem cells, like gut, skin and bone marrow. Mesenchymal
cells can self-renew by dividing and can differentiate into multiple tissues including bone, cartilage,
muscle etc. Mesenchymal stem cells are present in bone marrow. The advantages is that they are
pluripotent. For example:
- Neural stem cell → gives rise to neurons, astrocytes, oligodendrocytes.
- Cardiac stem cell → gives rise to cardiomyocytes, smooth muscle, endothelium.
They are besides that also non-tumorigenic, more differentiated (so further differentiation is easier),
can be patient-derived (autologous, so well tolerated). The disadvantage is that the disease can
affect the stem cells too in some cases.
Differentiation
It is driven by so-called paracrine factors. When proteins synthesized by one cell can diffuse over
small distances to induce changes in neighboring cells, the event is called a paracrine interaction, and
the diffusible proteins are called paracrine factors or growth and differentiation factors (GDFs).
Surface of the cell matters for differentiation:
- The area on which the cell can differentiate. E.g. on a smaller area the stem cell turns into an
adipocyte, while when it is differentiated on a bigger area it turns into an osteoblast.
- The stiffness. E.g. on a soft area it turns into an adipocyte and when it is differentiated on a
stiffer surface, it turns into a bone cell.
, - Topography, so basically the distribution of parts or
features on the surface of/within an organ /
organism / environment. For example, the
adhesion and differentiation of satellite cells to
skeletal muscle is promote by topography. In this
case the wavelength between the edges matters.
Chemical, physical or mechanical signals can be used to
instruct and direct stem cells to differentiate, as seen in the
image on the right. Instructive cues:
- Chemical
o Growth factors, chemokines, cytokines
o ECM components
o Chemicals
- Physical
o 2D, 3D scaffolds
o Scaffold roughness
o Scaffold wettability
- Mechanical
o Pressure/tension
o Shear stress
(Bio)chemical cues can be growth factors. For example the mesenchymal to epithelium transition
(MET) is driven by the growth factor BMP7, while the opposite, the epithelial-mesenchymal
transition (EMT) is driven by TGF-β.
Physical cues have to do with scaffolding. So is a 2D culture very different than a, more realistic, 3D
culture. The roughness/structure of the scaffold is of importance. The structurer of the gaps in
between determine how the cells are able to adhere. A scaffold supports the tissue and promotes
adhesion, survival and function of the cells. In tissue engineering and regenerative medicine the
scaffold is not permanent, it is biologically biodegradable and can be replaced by a physiological
matrix.
A mechanical cue is shear stress. It determines whether the cells are more longitudinal shaped in a
structure for example.
The aim of in vitro 3D tissue engineered constructs is to design new strategies for the repair of
human tissues and organs based on (biodegradable) polymers and/or humoral factors and (stem)
cells.
Implanted (bio) materials elicit a foreign body reaction (FBR), which leads to inflammation. For
implantation an incision has to be made. Because of this there is an activation of coagulation
processes. The implant is coated with serum proteins. Due to this the innate immune system
(=’aangeboren’) is activated. Macrophages get attracted/activated. The implant gets encapsulated by
fibroblasts. If possible, it will be degraded by macrophages, which leads to the resolution of the FBR.
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