Analysis of autopsy material after allogeneic mesencymal stromal cell infusions

by Alexey Bersenev on May 11, 2012 · 4 comments

in stem cell autopsy

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More than 200 clinical trials assessing safety and efficacy of mesenchymal stem cells (MSC) are currently ongoing around the world. Now we have many reports about safety of MSC infusions, but we still have no idea what is really going on with cells after infusion. Autopsy material can provide valuable information about cells fate, the mechanism of therapeutic action and long-term complications of cell therapy. Unfortunately, we are lacking reports about pathological finding from autopsies of patients, who underwent MSC-based therapies.

Katarina Le Blanc‘s group from Karolinska Institutet has published a very very important analysis of autopsy material from patients, who underwent MSC infusions. This report is not available in open access, so I’m going to summarize some very important points here.

The authors analyzed 18 patients with hematological malignancies and solid tumors, which underwent HLA-matched allogeneic MSC infusions to treat/ prevent complications of hematopoietic stem cell transplantation (GVHD, hemorrhagic cystitis and some others). All patients died in 3 – 408 days (median 21 days) after the last MSC infusion. Donor’s MSC’s DNA was detected by PCR in multiple tissues. The results of this analysis are the following:

1. No solid tumors (of any origin) or ectopic tissue formation was observed.
Lymphoproliferative disorder was diagnosed in two patients, but no link to infused MSC was found.

2. Tissues from 8 out of 18 patients (44%) were positive for MSC donor DNA. Quantative analysis was done in 6 cases. Only one patient had MSC donor DNA > 1/1000 cells. Positive MSC were found mostly in the lungs, lymph nodes and intestine. MSC donor DNA in bone marrow was detected only in one case.

Histological examination of engrafted MSCs was not possible due to the scarcity of the cells. We can therefore not conclude that the DNA detected represents true MSC engraftment.

3. There were no correlation found between MSC engraftment (donor DNA) and treatment response:

… of the fifteen patients available for PCR analysis, three had shown a complete response to MSC therapy, six a partial response and six were classified as non-responders.

4. Detection of MSC donor DNA was negatively correlated with time after infusion and autopsy/ biopsy.

The bottom line: Intravenous infusion of matched allogeneic MSC does not cause severe complications, such as tumor or ectopic tissue formation due to rapid clearance from the recipient. More likely, allogeneic MSC act as “medicinal cells” shortly after infusion and do not engraft in the tissues. The persistence of donor’s MSC in recipient does not correlate with treatment efficacy:

The function of MSCs appears to be mediated through a “hit and run” mechanism rather than through sustained engraftment in the injured tissues.

Overall, this remarkable study is very unique and well done! Highly recommended to read and cite!

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{ 4 comments… read them below or add one }

deev roman May 11, 2012 at 3:07 am

In bone tissue engraftment????

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Paul Knoepfler May 12, 2012 at 2:30 pm

This is a great piece, Alexey.
The data here provide some important answers. I hope other similar studies will be conducted to build on this. I wonder if patients were to survive and live decades, could those few remaining allogeneic cells cause health problems or would ultimately essentially all be “cleared”? I wonder if we could figure out the molecular details of the “hit and run” could a small molecule therapy substitute for the cells themselves? The no tumors finding is very encouraging because even though patients who live may not present clinically with a tumor you never know if they have one, but autopsy analysis is definitive.
Paul

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Glenn McGee May 12, 2012 at 6:04 pm

The tie to engraftment is interesting…I saw a major review article about to come out that analyzes the dozens of studies of the “homing” of MSCs and deals with this “hit and run” phenomenon with an emphasis on how the cell function is called for and regulated. I am blanking on the name of the lab at Penn that just did a great study on MSC homing as well.

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Maria Cabreira May 14, 2012 at 4:25 pm

Thanks for the posting! We were intrigued by our findings of MSC in the lymph nodes. This study supports ours.

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