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Organ-Specific Precursor Tissue
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Alternative source
Prof. Reisner's team at the Weizmann
Institute of Science has developed an approach using specific organ
precursor tissue as an alternative to full organ transplant. This
technology may also dramatically reduce the need for long-term use of
immunosuppressive drugs.
Tissera's use of organ-specific precursor
tissue could provide a therapeutic strategy to treat a wide range of
pathologies. The landmark technology could potentially provide a
constant source for new organs for transplantation.
To treat other diseases such as end-stage
renal disease or severe liver cirrhosis, a substantial mass of embryonic
tissue will be implanted so that it could mature into a functional
organ. This would potentially provide a substitute for full organ
transplants from donated organs.
Implanting healthy embryonic tissue that
will mature and produce missing proteins is seen as a therapy for many
diseases where a specific protein is not being produced in sufficient
quantities (type I diabetes, hemophilia, etc.).
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 Identifying
Tissue |
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Optimizing
Timing |
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The
Porcine Alternative
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Identifying Tissue
At a certain
point in embryonic development, stem cells differentiate and commit to a
particular developmental pathway leading to the formation of a specific
organ. These are referred to as “committed organ-specific precursors”
(“kidney precursor” cells, “liver precursor” cells and others).
In their study,
Prof. Reisner’s team was able to identify and transplant successfully
human and pig kidney precursor cells (stem cells destined to become
kidney cells), into mice.
Both human and pig tissue grew into well developed miniature kidneys.
The miniature kidneys were shown to produce diluted urine. In addition,
the risk of rejection – a common phenomenon in current transplantation
procedures – was greatly reduced since the blood supply within the
kidney was provided largely by the host rather than donor blood vessels.
 
Fig 2. Functional
kidney arising from 8 week old human embryo 8 weeks after
transplantation into mouse (macroscopic and microscopic view).
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Optimizing Timing
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When
harvesting precursor tissues, optimization of the timing of
tissue harvesting is a crucial factor that determines the
transplantation success.
Prof. Reisner's team pinpointed the ideal time
when human and pig embryonic cells commit to form kidney
precursor tissue. Experiments showed that porcine embryonic
cells that have gestated to week 4 and human embryonic cells
gestated to week 7-8 provided optimal results. Cells that
gestated for too short a time developed into disorganized
tissue (teratoma) that included non-kidney structures such as
bone, cartilage and muscle. Cells that had gestated too long
provoked an immune response. However, when human and pig
tissue was harvested at the appropriate time and then
implanted into mice, the tissue grew into miniature kidneys.
Importantly, the new tissue became vascularized
with small and medium capillaries growing mainly from
host animal cells. Vascularization from the host animal
reduces the likelihood or the severity of a future immune
response. The regenerated kidneys
exhibited normal appearance and were shown to produce
diluted urine.
After
growing the human and porcine kidney tissue in mice, the
scientists checked how human lymphocytes (fighter cells in the
immune system) might react to it. They injected human
lymphocytes into immuno-deficient mice (that have no immune
system and thus do not interfere with the immune response).
The findings were encouraging: as long as the kidney
precursors were transplanted within the right time range, the
lymphocytes did not attack the new pig or human kidneys –
despite the fact that lymphocytes and kidney precursors
originated from different donors. Immune rejection was also
tested in normal mice and was shown to be reduced compared to
that induced by precursors that had gestated longer. Within
the optimal time range identified in Prof. Reisner’s lab,
harvested tissue does not contain antigen-presenting cells
that the body recognizes as foreign. These cells, which
originate in the blood system, reach a developing kidney only
after ten weeks in humans.
Fig 4. Lack of staining with antibodies against
human CD3 (human immune cell marker) and preserved tubuli and
glomeruli in transplant originating from 8 week human embryo
and 4 week pig embryo proves that a host immune response was
not elicited against these tissues.
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The
Porcine Alternative
Human tissue produces human proteins that may
have a better therapeutic potential than porcine tissue that
produces somewhat different proteins. In treating some
diseases, these differences may be significant; in treating
other diseases, they are not.
For these reasons, Prof. Reisner’s lab has
conducted parallel experiments using human and porcine tissues
and Tissera plans to continue to develop both human and
porcine alternatives. Prof. Reisner’s experiments indicate
that the level of immune response in
xenotransplants (human and porcine transfer to mice) of
early embryonic tissue has been minimal.
In the past, there has been considerable
concern that cross-species transplantation (xenotransplantation)
may lead to the spread of viruses or may induce an immune
response. To date, under careful scrutiny, there have not been
reports of disease transfer.
The advantage of porcine tissues is that pigs
may be a preferred source of tissue for certain clinical
applications. Pigs can be raised in controlled environments
and typically gestate five to ten embryos in each pregnancy.
Embryonic porcine tissue can be made available as needed.
 
Fig 3. Functional kidney arising from
4-week-old pig embryo, 8 weeks after transplantation into
mouse (macroscopic and microscopic view).
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