Arthritis and musculoskeletal disorders constitute a major cause of disability and the burden of musculoskeletal diseases will increase with an increasing ageing population.22 Stem cells remain at the forefront of efforts in Regenerative Medicine, based on a conviction that this technology can provide an effective treatment paradigm for major diseases where there is still an unmet need.3
In 2017 the first prospective, single blind, placebo-controlled trial of bone marrow aspirate concentrate for knee osteoarthritis described a positive clinical outcome.31 A recent review of 1500 papers on stem cell therapy in orthopaedics revealed, that studies reported information on only 42% (range, 25%-60%) of the variables included within established minimum reporting standards, leaving it unclear, which amount of stem cells was really harvested and injected.25, 29 A higher donor-site cell count correlates with a better outcome.8, 14, 18, 19, 27, 35 In hemato-oncology, where bone marrow transplantations are performed routinely since decades, elderly patients show inferior mobilization rates and inferior outcome in some studies.1, 28,14 Likewise, in a mice model an age-related fatty degeneration of the bone marrow was described.21
The current study looked at the donor site of 873 healthy patients (without bone marrow diseases), applicable for orthopaedic interventions, to understand the vitality and the quality of the bone marrow derived (stem) cells.
Age and cell counts
Due to its large sample size this study is the first to establish a normal range of leukocytes and CD34+ stem cells in bone marrow aspirate (BMA) in the average population. The amount and vitality of bone marrow derived leucocytes and the number of mononuclear cells (stem cells) do not deteriorate over age. The formerly described lower mobilization rate of bone marrow derived (stem) cells in the elderly in some studies1, 28 conflicts with a recent study, where little of the parameter variability could be explained by age.5 Our finding, that the number of bone marrow derived leucocytes remains stable in adults was confirmed in a prior study with 24 goats, but we did not find further papers referring to humans.2
Vitality
The vitality of bone marrow derived cells was always high (87-91%) in all age groups using FACS (fluorescence-activated cell sorting) analysis. Regarding dental pulp stem, the proliferation rate decreases in elderly patients.36 We could not confirm this finding in bone marrow derived cells. It is well known, that jawbones have an different bone metabolism.32
Correlation / Predictor
Stem cells are mononuclear cells and therefore a 7.4% fraction (1 / 13.5) of the bone marrow derived leucocytes, as we demonstrated.
To our knowledge no prior study described the positive and strong correlation (p<.001, r2=822) between both parameters. Since stem cells can only be identified using specific CD antigen sets (CD 34, CD 90, CD 45, CD 107,…), which is costly and laborious, this correlation can be utilized, to predict the amount of stem cells based on the number of bone marrow derived leucocytes alone, which is much easier. As a matter of fact, only a negligible share of publications reports the absolute number of stem cells used per patient.29 Using the new described correlation, a much cheaper possibility exists, to assess, if a specific patient has a high or low stem cell number, since counting leukocytes can be done in any operating room, but counting stem cells requires at least a FACS analysis.
Limitations:
Since this was a retrospective study, we were not able to assess any social data (body weight, sport habits, smoking status,…). We did not perform colonization and differentiation experiments, since the lack of a specific MSC marker and the low frequency of MSCs in bone marrow necessitate their isolation by in vitro expansion.
Further research is needed to link clinical outcome with the absolute number of bone marrow derived leukocytes and stem cells since it is not yet clear, if the heterogenous clinical results of individual patients are linked to the heterogenous bone marrow derived stem cell counts. It remains speculative if patients with higher cell counts will have better outcomes and might therefore be better suitable for stem cell operations.