Liver stem cells as they relate to regeneration

For both HCV disease, and for transplant patients the question of liver regeneration becomes an important one.

Especially for those who are given a live donor transplant, where they will still have to regrow 2/3 of a liver (and do grow it back in a year or so's time) the question of how liver cells grow and divide, and how to stimulate the body's own stem cells becomes as important topic.

Evidently, the greater the injury, the greater the chance of stem cells coming to the rescue.
Although research into growing stems for individual patients is a long way off there is one pharmaceutical which does stimulate stem cells to migrate to the liver, and that is HGH, (Human Growth Hormone) only available in injection form currently.
There is of course a greater chance of aberant cells forming as well, should dosing be excessive, or the immune system weak and unable to recognize the same.

In any case, it's an interesting topic I hope will get the research dollars it deserves.

Thought maybe we could post things relating to this topic on this thread.

for consideration:

>>>>>>>>>>>>>Is There a Liver Stem Cell?
by Stewart Sell
Department of Pathology and Laboratory Medicine, University of Texas Health Science Center, Houston, Texas 77030

The role of a putative liver stem cell in liver regeneration and carcinogenesis is reviewed. There is increasing evidence that there is a liver stem cell that has the capacity to differentiate into parenchymal hepatocytes or into bile ductular cells. These stem cells may be activated to proliferate after severe liver injury or exposure to hepatocarcinogens. They are not activated by moderate liver injury, which is repaired by proliferation of mature heaptocytes. Exposure to most chemical hepatocarcinogens results in proliferation of a small morphologically indistinct cell population termed "oval cells." These cells have been shown to have the capacity to differentiate into hepatocytes or into ductular cells. The origin of these cells appears to be from transition duct cells, but there is also evidence of an even less mature periportal liver stem cell. Study of the development of these cells during carcinogenesis indicates that liver cancer arises from oval cells by aberrant differentiation of stem cells.
end.

So, judging from the above, I would say the live donor recipient might have a better chance of replacing the needed 2/3 of a liver with more of ones own stem cells and ergo ones own genetic material due to the greater injury calling upon that system to produce cells.
Ergo eventually rejection might be less of an issue for that group.
(this is just my theory based on the above explaination of the constructs. It could be wrong).

Now this brings up what researcch is there into oval cell stimulation as well. Hmm.
mb

[merryBe]

http://www.hopkinsmedicine.org/Press_releases/2004/06_01_04.html

bone marrow stem cells research at John Hopkins

[merryBe]

a genetic cure for liver cancer discovered through stem cell research and why we all need some little ELFs in our lives ; )))))))))))

http://www.sciencedaily.com/releases/2008/02/080208113917.htm

[mikesimon]

Regarding your hypothesis:
"So, judging from the above, I would say the live donor recipient might have a better chance of replacing the needed 2/3 of a liver with more of ones own stem cells and ergo ones own genetic material due to the greater injury calling upon that system to produce cells.
Ergo eventually rejection might be less of an issue for that group. "

From: Living-related versus deceased donor pediatric liver transplantation: a multivariate analysis of technical and immunological complications in 235 recipients.
Pediatric Liver Transplant Program, Université Catholique de Louvain, Saint-Luc University Clinics, Brussels, Belgium. 2007
"......At multivariate analysis: (1) type of donor (DD) was correlated with higher rate of artery thrombosis (p < 0.012); (2) biliary complication rate at 5 years was 29% and 23% for groups LD and DD, respectively (p = 0.451); (3) lower acute rejection incidence could be correlated with type of donor (DD) (p = 0.001), and immunosuppressive therapy (tacrolimus) (p < 0.001). We conclude that (1) according to the multivariate analysis, LT with LD provided similar patient and graft outcome, when compared to DD; (2) a higher rate of artery thrombosis and a lower rate of rejection were observed in group DD; (3) this study confirms the efficacy of tacrolimus for immunoprophylaxis, whatever the type of organ donor is."

From: Do graft type or donor source affect acute rejection rates after liver transplant: a multivariate analysis.
Department of Surgery, University of Minnesota, Minneapolis, MN, USA. 2008

"We looked at acute rejection (AR) rates in adult liver transplant recipients to determine if graft type (whole liver vs. partial liver) or donor source (living vs. deceased donor) influenced the risk for AR. Between 1999 and 2005, we performed 292 whole liver transplants from a deceased donor (DD-WL) and 91 partial transplants, either from a living donor (LDLT, n = 59) or split liver from a deceased donor (DD-SL, n = 32). Pediatric recipients were not included. The groups were well matched by age and type of liver disease (p = ns), but mean model for end-stage liver disease (MELD) scores were higher in the DD-WL vs. LD recipient groups (p < 0.01). Immunosuppression was similar for all. AR rates at 12 months post-transplant were lower in the LDLT group (10.0%) vs. the DD-WL group (16.5%, p = 0.10), although this was not statistically significant. AR rates in the DD-SL transplant group (12.8%) were intermediate compared with the two other groups and not statistically different from either group (p = ns). By multivariate analysis, however, neither graft type (partial vs. whole) nor donor source (LD vs. DD) seemed to have an impact on the risk for AR. The only factor that was associated with an increased risk for AR was not using induction therapy."

From: Marked Differences in acute cellular rejection rates between living-donor and deceased-donor liver transplant recipients.
Recanati/Miller Transplantation Institute, The Mount Sinai Medical Center, New York, NY 10029, USA. 2005

"BACKGROUND.: Due to ongoing organ donor shortage, an increasing number of adult live-donor liver transplants (LDLT) are being performed. The aims of this study were to compare the incidence of ACR between recipients of live- and deceased-donor liver transplants, and to note any differences in ACR among related and unrelated living-donor recipients. METHODS.: Sixty-four adults undergoing LDLT between 1998-2001 were closely matched with a deceased recipient. Statistical comparisons in ACR between the live- and deceased-donor groups were based on the differences between the ACR rates of each LDLT patient and the corresponding matched deceased recipient. Analyses were performed separately for pairs in which the living donor was not related to the recipient, was a nonsibling relative, or was a sibling. RESULTS.: Live- and deceased-donor recipients underwent a similar number of liver biopsies. In all, 16/50 (32%) of the biopsied LDLT patients had ACR compared to 36/49 (73%) of the deceased-donor recipients. ACR rates of living donors and their deceased-donor matches did not differ significantly for the unrelated living donors, but did differ for the nonsibling related (P=0.03) and the sibling LDLT (P=0.03). The results were similar when comparing rates of high-degree ACR for unrelated, nonsibling related, and sibling pairs. High-degree ACR differences in the sibling LDLT group were significantly greater than in the nonsibling group (P=0.05). CONCLUSIONS.: Rates of ACR and high-degree ACR are decreased in living-related liver transplant recipients. This difference is likely genetically related as ACR rates are lower in recipient-donor pairs of increasing genetic similarity."

It doesn't appear as though your theory is borne out in the real world experience - at least not in the information I found

Mike

[merryBe]

well, I sort of see that, except that the first study is pediatric, and I wonder if the factors in liver size and immune functions in babies would translate into identical adult outcomes. Certainly more thrombosis isn't a desirable, but this may be a factor of the microsurgery aspects. After all, transplant is very complex, in a baby more so due to the size of the veins and arteries being grafted...so more chance for arterial injury where the body is so delicate.

But the 3 studies conclude saying that both the genetic similarity and the induction therapy are the chief determinates, not LD vs. DD. meaning, yes the LD does not cause more of ones own stems to form tissue necessarily, perhaps becuase the LD does not register as a greater injury for some reason. Yet still, the genetic similarity appears the ultimate determinate in the last study.
  
So then, if stem cell transplants or stimulation occurs, that creates more genetically similar tissue also does it not?  Ergo more research into how to turn those genes on for cancer or transplant patients still makes sense.\

As to the induction therapy in the second all adult study, it is my understanding that this is practiced for cancer patients, so I'm unclear as to how this really relates to the average HCV TP patient unless they are referencing INF/riba therapy in advance of transplantation, It appears unclear whether the study involved only TP patients having cancer, so I'm unsure how applicable the information then becomes to others not in need of induction.

If you can clarify whether induction applies to HCV people Mike, I'd appreciate that.
It was my understanding that if INF tx did not reach the goal of SVR then there was no need of tx up until the time of TP, in fact that it was better to give that a rest, and retreat after TP was accomplished as one would stand a better chance of then reaching SVR given a healthier liver with a lesser VL to begin with.

Back to the point of my ponderings...was whether genetically similar tissue would decrease the rate of rejection, or increase the chances of weaning, or not experiencing rejection, and the last study you posted seem to agree at least that the greater the genetic similarity the better chances for the patient.Which means I'll continue to read up on stem cells...there's a guy in Newcastle doing some interesting work..name escape me just now..

thank you for the studies
mb

[mikesimon]

Induction therapy: The administration of a brief course of high-dose immunosuppression in the early posttransplant period. Induction therapy precedes and overlaps with less intense long-term maintenance immunosuppression.

Mike

[mikesimon]

From what I have read tolerance is more likely to be achieved in liver transplantation than it is in transplantation of other organs.
With that in mind I am nevertheless posting the following articles which involve renal transplantation. The reason is to attempt to address your question:

"Back to the point of my ponderings...was whether genetically similar tissue would decrease the rate of rejection, or increase the chances of weaning, or not experiencing rejection, and the last study you posted seem to agree at least that the greater the genetic similarity the better chances for the patient."  

I think that this issue is far too complex to make broad sweeping assertions regarding transplant outcome based on genetic similarity. I believe these articles reflect the complexity of this subject.

The Role of Donor-Recipient Relationship in Long-Term Outcomes of Living Donor Renal Transplantation.
Miles CD, Schaubel DE, Liu D, Port FK, Rao PS.

1 Department of Medicine, Nebraska Medical Center, Omaha, NE. 2 Department of Biostatistics, University of Michigan, Ann Arbor, MI. 3 Scientific Registry of Transplant Recipients, Ann Arbor, MI. 4 Arbor Research Collaborative for Health, Ann Arbor, MI. 5 Department of Medicine, University of Michigan, Ann Arbor, MI.

BACKGROUND.: Graft failure related to acute and chronic rejection remains an important problem in transplantation. An association has been reported between microchimerism and the development of tolerance. Since it has been established that cells of fetal origin can be found in maternal tissues long after parturition, and cells of maternal origin may persist for years in offspring, we hypothesized that this fetal-maternal microchimerism may confer tolerance and thus less graft loss for kidneys transplanted between mothers and their offspring. METHODS.: We used data from the Scientific Registry of Transplant Recipients to compare death-censored graft survival among recipients of living-related renal transplants sharing at least one human leukocyte antigen (HLA) haplotype with their donor. A total of 23,064 such transplants were reported from 1995 to 2004. A Cox proportional hazards model was constructed to compare death-censored graft survival among the following donor-recipient pairings: child-to-mother, child-to-father, mother-to-child, father-to-child, 1-haplotype matched siblings, and HLA-identical siblings. RESULTS.: HLA-identical sibling recipients had the best survival, but results for the child-to-father group were not significantly worse (hazard ratio=1.07, P=0.47). Mother-to-child transplants had the poorest graft survival (hazard ratio=2.61, P<0.0001). We found no evidence of tolerance to kidneys transplanted between mothers and offspring. CONCLUSIONS.: Our analysis of 1-haplotype matched living-related renal transplants argues against tolerance to organs based on fetal-maternal microchimerism. Mechanistic studies examining the relationship between chimerism and immune sensitization would be useful to explore our results, and may contribute to a better understanding of tolerance.



Nephrol Ther. 2008 Feb;4(1):72-6.Click here to read Links
    [Transplantation from a living related donor: Results]
    [Article in French]

    Hourmant M, Kolko A.

    Service de néphrologie et d'immunologie clinique, CHU de Nantes, 44093 Nantes cedex, France. [e-mail]

    The results of transplantation from a living donor (LDT) are constantly better than those of cadaveric transplantation (2004 Report of the French Agency of Biomedicine: graft survival 80 versus 63% at 10 years). Transplantation from an HLA-identical sibling is in any case the best combination, but there is no significant difference in graft survival when the donor is a parent, a child, a non HLA-identical sibling, a spouse or an unrelated person. The reasons for these better results are several: the quality of the kidney transplant, the absence of brain death, the advantage of a programmed surgery and of preemptive transplantation. It is admitted now that HLA compatibility plays a minor role. As in cadaveric transplantation, acute rejection, delayed graft function, pretransplant HLA immunisation, age of the donor and the recipient and possibly the discrepancy between the weight of the donor and the recipient are determinants of transplant outcome.

1: Transplantation. 2007 Oct 27;84(8):972-80.Click here to read Links
    Parental donors in live-donor kidney transplantation associated with increased rejection rates and reduced glomerular filtration rates.
    Lim WH, Chang SH, Coates PT, McDonald SP.

    Department of Renal Medicine, Sir Charles Gairdner Hospital, Western Australia, Australia. wai.***@****

    BACKGROUND: Living unrelated and related kidney transplantation has been shown to have similar allograft survival. However, the effect of donor-recipient relatedness in living-related and unrelated kidney transplantation on graft and patient survival remains uncertain. METHODS: Using Australia and New Zealand Dialysis and Transplant Registry, primary living renal transplant recipients in Australia between 1995 and 2004 were studied (n=1989). Donors were categorized according to their relationship with recipients: parent (n=606), child (n=103), spouse (n=358), sibling (n=656), other living-related donors (n=81), and other living-unrelated donors (n=185). Outcomes analyzed included the presence of rejection at 6 months, estimated glomerular filtration rate (eGFR) at 1 and 3 years, graft survival, and patient survival. RESULTS: A greater proportion of renal transplant recipients from parental and spousal donors were transplanted preemptively. Donor groups had no relationship with graft or patient survival. Parental donors were associated with an increased relative odds of acute rejection (odds ratio 1.69, 95% confidence interval 1.13-2.53, P=0.009) and a lower eGFR at both 1 and 3 years (coefficient -2.99 and -5.68, respectively; P<0.0001) compared to other donor groups (reference sibling donor group). CONCLUSIONS: This study has established that donor-recipient relatedness in both related and unrelated living kidney transplantation had no significant effect on graft and patient survival. Parental donors were associated with a higher relative risk of rejection and lower eGFR in the transplant recipients, although these findings did not translate to a worse graft outcome.

Mike

[merryBe]

thanks...well, this is why I called these my ponderings and not hypothesis...

>>>>>>>>HLA-identical sibling recipients had the best survival,

which of course makes sense being genetic twins...but that only argues for more stem cell research.

The rest of the study does make the point well for kidneys not being effected one way or another.

The question that might remain is does the unique ability of the livers regenerative skills bring in a growth factor through it's oval and stem cells that might bring it a far greater chance of survival were the right secretogues or peptides or whatever found that would stimulate the graft.

Since the liver possesses power the other organs don't, I think that would be very exciting research to see developed and to follow. Don't you agree?

Also have seen articles now on the umbilical cord stem cells grafting to liver tissue much better than fatal stems. That should make a lot of people happy.
maryb

[mikesimon]

I never meant to suggest that I am against stem cell research because I most certainly strongly support intense research in this area. Mike

[merryBe]

I never thought you were....there are believers who are against harvesting fetus's for such uses....But I think since the umbelical cord cells are proving superior in every study that the whole thing is quickly becoming an non-issue there.

I think it's interesting too that they are trying to get all parents to allow for freezing and registry of the cord cells. This not only allows the child more therapy opportunity should they have need, but will one day make donors far easier to find for everyone.
If they have a pool of millions, it will make finding a good match for say bone marrow go much easier, and safe countless lives.
mb

[eureka254]

"The results of transplantation from a living donor (LDT) are constantly better than those of cadaveric transplantation (2004 Report of the French Agency of Biomedicine: graft survival 80 versus 63% at 10 years). "
--------
As I understand the above relates to kidney transplant, but I wonder if you happen to have any data relating to living-donor liver tp vs cadaver liver tp?
With thanks in advance,
~eureka

[mikesimon]

Without researching I would guess that the numbers for graft and patient survival are pretty similar for living vs cadaver liver transplant. I am not familiar with the French system but generally speaking here is the US the advantages for a living donor might be 1) less time waiting for a liver and thus a healthier recipient  2) less risk of a non functioning cadaver liver due to ischemia and 3) perhaps less rejection risk with a close relative as the donor.
I do not know for certain but I would strongly suspect that the 10 year graft survival in liver transplants - living vs cadaver - would not be as different as your numbers reflect. But, honestly I don't have the data in front of me so it well could be that dramatic of a difference. I'm just too lazy to research it. I want to ride my bike if it doesn't rain.
Mike

[eureka254]

I've become interested in learning more about LDT since hearing that the Transplant Center that follows my husband now has a physician on staff w/experience in LDT.  Thanks for your input.

Sunday is the perfect day to be lazy :).  Hope the weather holds out for you -- enjoy the ride on that beauty of a bike.
~eureka

[Charan620]

Hi I came across a link which states that Stem cells treatment can even cure cirrhosis. Not sure how reliable it is. Is anybody aware of it? If its true than its really a boon for lots of us who is suffering from fibrosis/cirrhosis.

Stem cell therapy does cure liver cirrhosis and spinal cord injury provided the patient is young and the level of injury is low, said Dr Samuel J K Abraham, Director of Nichi-in Center for Regenerative Medicine (NCRM),

Vinay