We blogged recently about Mesenchymal Stem/Stromal Cell (MSC) Misconceptions that are holding the translational cell therapy field back, as identified by Donald Phinney and Luc Sensebé. Since we have come to market with our own hMSC product lines, we have spoken with hundreds of MSC researchers and engineers, and we have compiled our own set of misconceptions that we think build off of Dr. Phinney’s and Dr. Sensebe’s initial concept. This blog post is to share some of the market-based feedback that we have received.
To the list that was published in Cytotherapy, we would like to contribute the following list to the conversation:
1. Tracking MSC passage number is an accurate and reliable means of tracking cell age and standardizing experimental workflow
In many research laboratory environments, cellular age is most often tracked by the number of times a cell has been passaged; however, Passage Number is quite imprecise and not very acceptable as one gets into regulated environments such as translational clinical activities. It is generally accepted that tracking the Population Doubling Level (PDL) or Cumulative Population Doublings (CPD) of primary cells is a best practice on understanding cellular age in vitro. Since it is well documented that PDL impacts hMSC function (see here, here and here), in order to drive consistency into experiments, it has become a best practice to perform experiments or develop products with cells in a consistent range of population doublings where the cell function of interest is still robust. Furthermore, regulatory agencies are beginning to require reporting of PDLs, or at least cell seeding and harvest densities, for primary cells intended for therapeutic use. In an effort to drive adoption of PDL tracking and reporting, we’ve created a Best Practices Educational Powerpoint, and free, easy-to-use PDL calculator worksheet we’re happy to share with colleagues. For your copy, just email us at firstname.lastname@example.org or subscribe to our blog!
2. Performing experiments with one MSC donor and/or lot is adequate for publication and moving forward with pre-clinical studies
Despite indications of clinical effectiveness of MSCs, there is repeated news of the failure of high-profile MSC trials to demonstrate efficacy in a number of therapeutic applications. It has been suggested that the large amount of intra- and inter-donor variability in the MSC populations used in these trials may be responsible for their falling short of expectations despite highly encouraging in vitro and in vivo pre-clinical data. Thus, to ensure the robust production of functional MSC products over a range of applications, experiments should be conducted and systems validated with MSCs from several donors. It has been reported that best practices to qualify a manufacturing process should include “at least 3-5 donors”, and it is likely that proper Validation will require many more, and that donor selection may be required (i.e. not every donor will work in the manufacturing process). This is why we, at RoosterBio, believe in providing a number of donor MSC lots, ranging in age and sex, for use in our customer’s research and development experiments.
3. MSCs accelerate cancer…..MSCs can combat cancer
Whichever side of the aisle you find yourself on, the truth is likely somewhere in the middle depending on 1) the specific MSC population being used, 2) the way(s) in which this MSC population has been modified/altered, and 3) how this MSC population is being administered therapeutically. There are exciting developments occurring in this research area, and the next 5-10 years will yield dramatic changes in how MSCs are used in cancer therapy.
4. MSC senescence as a Quality Parameter
In the blog StemCellAssays.com, Alexey brings to light the idea that many researchers are discussing at meetings and now publishing on – which is that senescent hMSCs should not be used as therapies due to lack of function. We would agree that senescent cells have no right being incorporated into cell therapy products, but our view is that manufacturing processes should be designed so that cells do not expand to the level that senescence is a problem (Quality by Design and not Quality by Testing). Senescent cell cultures are horribly expensive to maintain (due to media costs, the labor used to maintain, and incubation time) and would not be commercially viable, so the addition of a quality control test to examine senescence specifically would be overkill. If viability and potency are affected by senescence, then it would be picked up in standard cell count and potency assays – and it seems that additional testing would be adding costs without additional benefit. Now, this may be more a problem in academic centers or “stem cell tourism” centers that are performing autologous cell expansions without well qualified processes or proper QC/potency assays. If this is happening, then there are deeper problems to address.
To the above points, our saavy colleagues have added the following in comments from our blog and LinkedIn Group discussions on this topic:
1. Heterologous tissue transplantation [of MSCs] can be a panacea for many different types of tissue disorders, i.e., everything from stroke therapy to myocardial infarct repair. – James L. Sherley, Director, The Adult Stem Cell Technology Center, LLC
2. Mesenchymal STEM cell is equivalent to a mesenchymal PROGENITOR cell, which it is not. Case in point is proliferation potential. True stem cells have extended capabilities for self-renewal. Progenitor cells, on the other hand, are limited to Hayflick's limit. And the list of differences between stem cells and progenitor cells goes on and on and on and on. – Henry E. Young, Professor, New Westminister College
3. Nice article. Thanks! This reference also makes the point that MSC surface markers are not specific. This link also makes the point that in vitro MSC differentiation assays may not be predictive of in vivo outcomes. – Carl Simon, NIST
We are going to comment on each of these reader additions in a follow-up blog post. We know those of you in the MSC space out there must have more to add to this list, so c’mon. Hit us up with some new ones, and feel free to add your two cents to the points made here! J