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A Bad MSC Meta-analysis Is a Great Way to Learn About Stem
Cells

dai metaanalysis systemic review mesenchymal stem cells knee osteoarthritis

Some orthopedic surgeons have a bizarre love-hate relationship
going on with injection-based knee arthritis stem cell therapy
while others have embraced it. Let’s dig into this phenomenon
through a poorly accomplished meta-analysis published in a big
orthopedic journal and learn quite a bit about the actual science
of stem cells and knee arthritis in the process. Let’s jump
in.

The Love-Hate Relationship with Stem Cells

Some orthopedic surgeons have a strange relationship with stem
cells. The forward thinkers in the field have welcomed this major
disruption of their world and begun to help patients avoid
surgeries. Basically cannibalizing what they do because these less
invasive procedures can be better for their patients. On the other
hand, there are stalwarts who don’t like change and who view this
whole concept as a scam.

On the one hand, you can’t blame the stalwarts because
there’s a ton of fraud going on, which is a very real problem for
their patients. On the other hand, if these procedures are as
revolutionary as the legitimate players who publish research claim,
then their entire ortho world is about to be turned upside down. No
single document exemplifies this bizarre relationship better than a
recently published meta-analysis in the orthopedic journal
Arthroscopy.

What Is a Meta Analysis?

When there are many different studies published on a single
treatment, there’s a technique where you can pool all of that
data together from different studies and analyze it as one data
set. So for example, if you have 4 studies about treatment A, of
50, 100, 75, and 50 patients, you can lump all of those patient
results together to analyze data from 275 patients. The idea is
that a research project with 275 patients is more powerful than any
of the individual papers.

Hence a meta-analysis is a study of studies. As a result, these
are often used to drive public policy. As I show you today and
tomorrow, this new one published in a prestigious orthopedic
journal isn’t worth the paper it’s written on.

The New Paper on Stem Cell Treatment for Knee Arthritis

The authors of the new paper have created a striking title:
“Intra-articular Mesenchymal Stromal Cell Injections are no
Different than Placebo in the Treatment of Knee Osteoarthritis: A
Systematic Review and Meta-analysis of Randomized Controlled
Trials”. Hence, you don’t need to read that far to figure out
that this meta-analysis concluded that stem cell therapy for knee
arthritis didn’t work.

The authors took 14 different papers published using the term
“stem cell” where knee arthritis was treated (1). They then
analyzed the data in several different ways. As the title
telegraphs, ultimately, they concluded that the therapy was
ineffective for knee arthritis. However, digging deeper and
looking under the hood shows that the study proved no such thing.
In fact, it’s a huge mess.

Lumping Together Vastly Different Therapies

This field of regenerative medicine has always suffered from a
severe naming problem. It’s because of that issue that many
clinics can scam patients by delivering completely different
treatments and then slapping the term “stem cells†on the
therapy. However, it’s not just patients that confuse all of
this, but physicians and researchers who should know better.

The main issue that causes this particular paper to fall apart
in taters is simple. The authors called all of the therapies from
the 14 papers “mesenchymal stem cell injectionsâ€. By doing
that, they created a fiction that all of these treatments were the
same, when in fact they couldn’t be more different.

As reviewed above, the hallmark of a meta-analysis is that it
lumps all of the data together because the therapy is the same or
very similar. However, this study grouped together the following
therapies from 14 studies that have little to do with each
other:

  • Cultured expanded bone marrow MSCs
  • Culture-expanded adipose MSCs
  • Stromal Vascular Fraction (SVF)
  • Culture expanded placental MSCs
  • Culture expanded umbilical cord MSCs
  • Bone Marrow Concentrate (BMC) with PPP

Just going over why these therapies are vastly different and
can’t scientifically be aggregated will teach a tremendous amount
about stem cells. The differences can be broken down into three
main categories:

  • Processed Cell Mixtures
  • Cultured Expanded and Isolated Cells
  • Different Cell Sources

Let’s now analyze why these treatments are HUGELY
DIFFERENT.

Processed Cell Mixtures

Two of the therapies above contain mixtures of lots of cells
where the minority of those cells are “mesenchymal stem cellsâ€.
These are SVF and BMC. These are dramatically different in many
ways.

SVF is created by digesting fat tissue to break down the
structural collagen and then centrifuging out the cells. What you
get is a mixture of different white blood cells, red blood cells,
macrophages, hematopoietic stem cells, other cells, and some
mesenchymal stem cells (2).

Bone marrow concentrate is created by taking bone marrow
aspirate (the liquid portion of the bone marrow) and centrifuging
it to isolate the buffy coat. That contains a mixture of different
white blood cells, red blood cells, macrophages, hematopoietic stem
cells, other stem cells, progenitor cells, and some mesenchymal
stem cells (5).

First, the percentage of mesenchymal stem cells differs between
these two. While fat has more of these, the MSCs in the bone marrow
are more efficient at cartilage repair (6-18). Second, there are
vast differences in the non stem cell components of these mixtures.
For example, while SVF is poor in hematopoietic stem cells (HSCs),
bone marrow is rich in these cells. So in the end, these cell
mixtures are as different as two different drugs (19,20).

In addition, if we just took one of these mixtures and tried to
compare just that type across different bedside machines there
would also be vast differences. For example, a study I performed
with a Stanford researcher several years back found huge
differences between different BMC mixes used in clinical practice
(5).

Cultured Expanded and Isolated Cells

If the above therapies are a mix of different cells, this
category is the opposite. Here, the above products of tissue
digestion and centrifugation are then plated in tissue culture to
isolate only the adherent MSCs. This is then repeated multiple
times until you get a “pureish†mixture of cells that are
called MSCs.

We still have the same problems as above, as the adipose MSCs
will perform differently than the bone marrow cells which will
perform differently than the placental cells which will perform
differently than the umbilical cord cells (3, 4, 21-23). In fact,
how you grow these cells will also change their final properties on
the body. For example, were they grown in a culture media that’s
from a different animal? (24) The same animal? The same patient or
a different patient? With exogenous growth factors or not? All of
these choices produce different cell lines (25, 26).

Different Cell Sources

As I alluded to above, we have four different cell sources
here:

  • Adipose
  • Bone marrow
  • Placenta
  • Umbilical cord

At best these MSCs are distant kissing cousins rather than
identical twins. For example, if we take the ability of these cells
to suppress inflammation, they are all massively different. There
are also other cell properties that make these cells for all
intents and purposes, different therapeutics (27-32).

A Meta-Analysis of Different Therapies?

Pooling data on a specific therapy from different studies
obviously requires that the therapy is the same. Given that these
authors looked at 14 studies that used six very different
therapies, the paper falls apart at it’s most basic critique.
Meaning that it isn’t a meta-analysis and the data can’t be
pooled or even compared head to head.

How Did this Paper Get Published?

Arthroscopy is a high impact factor orthopedic journal. Did the
reviewers not understand that these were VERY different therapies?
Could they be that oblivious to what’s published in the
literature?

This brings me back to my initial thoughts. The publication of
research is often very political. Does one side or another of an
issue want the message to get out there and are they willing to
overlook a few nasty warts to get the message published? In this
case, this paper fails at being able to support its most basic
structural concepts, yet somehow it got greenlighted in a major
journal.

The upshot? This paper is a mess of gargantuan proportions.
I’ve covered only one issue here, but tomorrow I’ll uncover
many more. Hence, this article doesn’t actually show that these
therapies are ineffective. In fact, tomorrow, I’ll show you how
the paper actually shows the opposite.

_________________________________

References

(1) Dai W, Leng X, Wang J, Shi Z, Cheng J, Hu X, Ao Y.
Intra-articular Mesenchymal Stromal Cell Injections are no
Different than Placebo in the Treatment of Knee Osteoarthritis: A
Systematic Review and Meta-analysis of Randomized Controlled
Trials. Arthroscopy. 2020 Oct 21:S0749-8063(20)30846-X. doi:
10.1016/j.arthro.2020.10.016. Epub ahead of print. PMID:
33098949.

(2) Brown JC, Shang H, Li Y, Yang N, Patel N, Katz AJ. Isolation
of Adipose-Derived Stromal Vascular Fraction Cells Using a Novel
Point-of-Care Device: Cell Characterization and Review of the
Literature. Tissue Eng Part C Methods. 2017 Mar;23(3):125-135. doi:
10.1089/ten.TEC.2016.0377. PMID: 28177263.

(3) Wu C, Chen L, Huang YZ, Huang Y, Parolini O, Zhong Q, Tian
X, Deng L. Comparison of the Proliferation and Differentiation
Potential of Human Urine-, Placenta Decidua Basalis-, and Bone
Marrow-Derived Stem Cells. Stem Cells Int. 2018 Dec
13;2018:7131532. doi: 10.1155/2018/7131532. Erratum in: Stem Cells
Int. 2019 Mar 10;2019:1651506. PMID: 30651734; PMCID:
PMC6311712.

(4) Beeravolu N, McKee C, Alamri A, Mikhael S, Brown C,
Perez-Cruet M, Chaudhry GR. Isolation and Characterization of
Mesenchymal Stromal Cells from Human Umbilical Cord and Fetal
Placenta. J Vis Exp. 2017 Apr 3;(122):55224. doi: 10.3791/55224.
PMID: 28447991; PMCID: PMC5564456.

(5) Schäfer R, DeBaun MR, Fleck E, Centeno CJ, Kraft D,
Leibacher J, Bieback K, Seifried E, Dragoo JL. Quantitation of
progenitor cell populations and growth factors after bone marrow
aspirate concentration. J Transl Med. 2019 Apr 8;17(1):115. doi:
10.1186/s12967-019-1866-7. PMID: 30961655; PMCID: PMC6454687.

(6) Li Q, Tang J, Wang R, Bei C, Xin L, Zeng Y, Tang X.
Comparing the chondrogenic potential in vivo of autogeneic
mesenchymal stem cells derived from different tissues. Artif Cells
Blood Substit Immobil Biotechnol. 2011 Feb;39(1):31-8. doi:
10.3109/10731191003776769. Epub 2010 Nov 30. PMID: 21117872.

(7) Jakobsen RB, Shahdadfar A, Reinholt FP, Brinchmann JE.
Chondrogenesis in a hyaluronic acid scaffold: comparison between
chondrocytes and MSC from bone marrow and adipose tissue. Knee Surg
Sports Traumatol Arthrosc. 2010 Oct;18(10):1407-16. doi:
10.1007/s00167-009-1017-4. Epub 2009 Dec 18. Erratum in: Knee Surg
Sports Traumatol Arthrosc. 2014 Jul;22(7):1711-4. PMID:
20020100.

(8) Danisovic L, Varga I, Polák S, Ulicná M, Hlavacková L,
Böhmer D, Vojtassák J. Comparison of in vitro chondrogenic
potential of human mesenchymal stem cells derived from bone marrow
and adipose tissue. Gen Physiol Biophys. 2009 Mar;28(1):56-62.
PMID: 19390137.

(9) Vidal MA, Robinson SO, Lopez MJ, Paulsen DB, Borkhsenious O,
Johnson JR, Moore RM, Gimble JM. Comparison of chondrogenic
potential in equine mesenchymal stromal cells derived from adipose
tissue and bone marrow. Vet Surg. 2008 Dec;37(8):713-24. doi:
10.1111/j.1532-950X.2008.00462.x. PMID: 19121166; PMCID:
PMC2746327.

(10) Kim HJ, Im GI. Chondrogenic differentiation of adipose
tissue-derived mesenchymal stem cells: greater doses of growth
factor are necessary. J Orthop Res. 2009 May;27(5):612-9. doi:
10.1002/jor.20766. PMID: 18985688.

(11) Koga H, Muneta T, Nagase T, Nimura A, Ju YJ, Mochizuki T,
Sekiya I. Comparison of mesenchymal tissues-derived stem cells for
in vivo chondrogenesis: suitable conditions for cell therapy of
cartilage defects in rabbit. Cell Tissue Res. 2008
Aug;333(2):207-15. doi: 10.1007/s00441-008-0633-5. Epub 2008 Jun
17. PMID: 18560897.

(12) Kisiday JD, Kopesky PW, Evans CH, Grodzinsky AJ, McIlwraith
CW, Frisbie DD. Evaluation of adult equine bone marrow- and
adipose-derived progenitor cell chondrogenesis in hydrogel
cultures. J Orthop Res. 2008 Mar;26(3):322-31. doi:
10.1002/jor.20508. PMID: 17960654.

(13) Mehlhorn AT, Niemeyer P, Kaiser S, Finkenzeller G, Stark
GB, Südkamp NP, Schmal H. Differential expression pattern of
extracellular matrix molecules during chondrogenesis of mesenchymal
stem cells from bone marrow and adipose tissue. Tissue Eng. 2006
Oct;12(10):2853-62. doi: 10.1089/ten.2006.12.2853. PMID:
17518654.

(14) Hennig T, Lorenz H, Thiel A, Goetzke K, Dickhut A, Geiger
F, Richter W. Reduced chondrogenic potential of adipose tissue
derived stromal cells correlates with an altered TGFbeta receptor
and BMP profile and is overcome by BMP-6. J Cell Physiol. 2007
Jun;211(3):682-91. doi: 10.1002/jcp.20977. PMID: 17238135.

(15) Pleumeekers MM, Nimeskern L, Koevoet WL, Kops N, Poublon
RM, Stok KS, van Osch GJ. The in vitro and in vivo capacity of
culture-expanded human cells from several sources encapsulated in
alginate to form cartilage. Eur Cell Mater. 2014 Apr 6;27:264-80;
discussion 278-80. doi: 10.22203/ecm.v027a19. PMID: 24706178.

(16) Alegre-Aguarón E, Desportes P, García-Ãlvarez F,
Castiella T, Larrad L, Martínez-Lorenzo MJ. Differences in surface
marker expression and chondrogenic potential among various
tissue-derived mesenchymal cells from elderly patients with
osteoarthritis. Cells Tissues Organs. 2012;196(3):231-40. doi:
10.1159/000334400. Epub 2012 Mar 20. PMID: 22947769.

(17) Xie X, Wang Y, Zhao C, Guo S, Liu S, Jia W, Tuan RS, Zhang
C. Comparative evaluation of MSCs from bone marrow and adipose
tissue seeded in PRP-derived scaffold for cartilage regeneration.
Biomaterials. 2012 Oct;33(29):7008-18. doi:
10.1016/j.biomaterials.2012.06.058. Epub 2012 Jul 19. PMID:
22818985.

(18) Reich CM, Raabe O, Wenisch S, Bridger PS, Kramer M, Arnhold
S. Isolation, culture and chondrogenic differentiation of canine
adipose tissue- and bone marrow-derived mesenchymal stem cells–a
comparative study. Vet Res Commun. 2012 Jun;36(2):139-48. doi:
10.1007/s11259-012-9523-0. Epub 2012 Mar 4. PMID: 22392598.

(19) Li CY, Wu XY, Tong JB, Yang XX, Zhao JL, Zheng QF, Zhao GB,
Ma ZJ. Comparative analysis of human mesenchymal stem cells from
bone marrow and adipose tissue under xeno-free conditions for cell
therapy. Stem Cell Res Ther. 2015 Apr 13;6(1):55. doi:
10.1186/s13287-015-0066-5. PMID: 25884704; PMCID: PMC4453294.

(20) Mohamed-Ahmed S, Fristad I, Lie SA, Suliman S, Mustafa K,
Vindenes H, Idris SB. Adipose-derived and bone marrow mesenchymal
stem cells: a donor-matched comparison. Stem Cell Res Ther. 2018
Jun 19;9(1):168. doi: 10.1186/s13287-018-0914-1. PMID: 29921311;
PMCID: PMC6008936.

(21) Heo JS, Choi Y, Kim HS, Kim HO. Comparison of molecular
profiles of human mesenchymal stem cells derived from bone marrow,
umbilical cord blood, placenta and adipose tissue. Int J Mol Med.
2016 Jan;37(1):115-25. doi: 10.3892/ijmm.2015.2413. Epub 2015 Nov
19. PMID: 26719857; PMCID: PMC4687432.

(22) Vangsness CT Jr, Sternberg H, Harris L. Umbilical Cord
Tissue Offers the Greatest Number of Harvestable Mesenchymal Stem
Cells for Research and Clinical Application: A Literature Review of
Different Harvest Sites. Arthroscopy. 2015 Sep;31(9):1836-43. doi:
10.1016/j.arthro.2015.03.014. PMID: 26354202.

(23) Wegmeyer H, Bröske AM, Leddin M, Kuentzer K, Nisslbeck AK,
Hupfeld J, Wiechmann K, Kuhlen J, von Schwerin C, Stein C, Knothe
S, Funk J, Huss R, Neubauer M. Mesenchymal stromal cell
characteristics vary depending on their origin. Stem Cells Dev.
2013 Oct 1;22(19):2606-18. doi: 10.1089/scd.2013.0016. Epub 2013
Jun 22. PMID: 23676112; PMCID: PMC3780294.

(24) Joswig AJ, Mitchell A, Cummings KJ, Levine GJ, Gregory CA,
Smith R 3rd, Watts AE. Repeated intra-articular injection of
allogeneic mesenchymal stem cells causes an adverse response
compared to autologous cells in the equine model. Stem Cell Res
Ther. 2017 Feb 28;8(1):42. doi: 10.1186/s13287-017-0503-8. PMID:
28241885; PMCID: PMC5329965.

(25) Seo JP, Tsuzuki N, Haneda S, Yamada K, Furuoka H, Tabata Y,
Sasaki N. Comparison of allogeneic platelet lysate and fetal bovine
serum for in vitro expansion of equine bone marrow-derived
mesenchymal stem cells. Res Vet Sci. 2013 Oct;95(2):693-8. doi:
10.1016/j.rvsc.2013.04.024. Epub 2013 May 16. PMID: 23683731.

(26) Ben Azouna N, Jenhani F, Regaya Z, Berraeis L, Ben Othman
T, Ducrocq E, Domenech J. Phenotypical and functional
characteristics of mesenchymal stem cells from bone marrow:
comparison of culture using different media supplemented with human
platelet lysate or fetal bovine serum. Stem Cell Res Ther. 2012 Feb
14;3(1):6. doi: 10.1186/scrt97. PMID: 22333342; PMCID:
PMC3340550.

(27) Shariatzadeh M, Song J, Wilson SL. The efficacy of
different sources of mesenchymal stem cells for the treatment of
knee osteoarthritis. Cell Tissue Res. 2019 Dec;378(3):399-410. doi:
10.1007/s00441-019-03069-9. Epub 2019 Jul 15. Erratum in: Cell
Tissue Res. 2019 Aug 3;: PMID: 31309317.

(28) Sakaguchi Y, Sekiya I, Yagishita K, Muneta T. Comparison of
human stem cells derived from various mesenchymal tissues:
superiority of synovium as a cell source. Arthritis Rheum. 2005
Aug;52(8):2521-9. doi: 10.1002/art.21212. PMID: 16052568.

(29) Contentin R, Demoor M, Concari M, Desancé M, Audigié F,
Branly T, Galéra P. Comparison of the Chondrogenic Potential of
Mesenchymal Stem Cells Derived from Bone Marrow and Umbilical Cord
Blood Intended for Cartilage Tissue Engineering. Stem Cell Rev Rep.
2020 Feb;16(1):126-143. doi: 10.1007/s12015-019-09914-2. PMID:
31745710.

(30) Ma J, Wu J, Han L, Jiang X, Yan L, Hao J, Wang H.
Comparative analysis of mesenchymal stem cells derived from
amniotic membrane, umbilical cord, and chorionic plate under
serum-free condition. Stem Cell Res Ther. 2019 Jan 11;10(1):19.
doi: 10.1186/s13287-018-1104-x. PMID: 30635045; PMCID:
PMC6330472.

(31) DaniÅ¡oviÄ Ä½, BohÃ¡Ä M, Zamborský R, Oravcová L,
Provazníková Z, Csöbönyeiová M, Varga I. Comparative analysis
of mesenchymal stromal cells from different tissue sources in
respect to articular cartilage tissue engineering. Gen Physiol
Biophys. 2016 Apr;35(2):207-14. doi: 10.4149/gpb_2015044. Epub 2016
Feb 18. PMID: 26891275.

(32) Ibrahim AM, Elgharabawi NM, Makhlouf MM, Ibrahim OY.
Chondrogenic differentiation of human umbilical cord blood-derived
mesenchymal stem cells in vitro. Microsc Res Tech. 2015
Aug;78(8):667-75. doi: 10.1002/jemt.22520. Epub 2015 Jun 12. PMID:
26096638.

dai metaanalysis systemic review mesenchymal stem cells knee osteoarthritis

Some orthopedic surgeons have a bizarre love-hate relationship
going on with injection-based knee arthritis stem cell therapy
while others have embraced it. Let’s dig into this phenomenon
through a poorly accomplished meta-analysis published in a big
orthopedic journal and learn quite a bit about the actual science
of stem cells and knee arthritis in the process. Let’s jump
in.

The Love-Hate Relationship with Stem Cells

Some orthopedic surgeons have a strange relationship with stem
cells. The forward thinkers in the field have welcomed this major
disruption of their world and begun to help patients avoid
surgeries. Basically cannibalizing what they do because these less
invasive procedures can be better for their patients. On the other
hand, there are stalwarts who don’t like change and who view this
whole concept as a scam.

On the one hand, you can’t blame the stalwarts because
there’s a ton of fraud going on, which is a very real problem for
their patients. On the other hand, if these procedures are as
revolutionary as the legitimate players who publish research claim,
then their entire ortho world is about to be turned upside down. No
single document exemplifies this bizarre relationship better than a
recently published meta-analysis in the orthopedic journal
Arthroscopy.

What Is a Meta Analysis?

When there are many different studies published on a single
treatment, there’s a technique where you can pool all of that
data together from different studies and analyze it as one data
set. So for example, if you have 4 studies about treatment A, of
50, 100, 75, and 50 patients, you can lump all of those patient
results together to analyze data from 275 patients. The idea is
that a research project with 275 patients is more powerful than any
of the individual papers.

Hence a meta-analysis is a study of studies. As a result, these
are often used to drive public policy. As I show you today and
tomorrow, this new one published in a prestigious orthopedic
journal isn’t worth the paper it’s written on.

The New Paper on Stem Cell Treatment for Knee Arthritis

The authors of the new paper have created a striking title:
“Intra-articular Mesenchymal Stromal Cell Injections are no
Different than Placebo in the Treatment of Knee Osteoarthritis: A
Systematic Review and Meta-analysis of Randomized Controlled
Trials”. Hence, you don’t need to read that far to figure out
that this meta-analysis concluded that stem cell therapy for knee
arthritis didn’t work.

The authors took 14 different papers published using the term
“stem cell” where knee arthritis was treated (1). They then
analyzed the data in several different ways. As the title
telegraphs, ultimately, they concluded that the therapy was
ineffective for knee arthritis. However, digging deeper and
looking under the hood shows that the study proved no such thing.
In fact, it’s a huge mess.

Lumping Together Vastly Different Therapies

This field of regenerative medicine has always suffered from a
severe naming problem. It’s because of that issue that many
clinics can scam patients by delivering completely different
treatments and then slapping the term “stem cells†on the
therapy. However, it’s not just patients that confuse all of
this, but physicians and researchers who should know better.

The main issue that causes this particular paper to fall apart
in taters is simple. The authors called all of the therapies from
the 14 papers “mesenchymal stem cell injectionsâ€. By doing
that, they created a fiction that all of these treatments were the
same, when in fact they couldn’t be more different.

As reviewed above, the hallmark of a meta-analysis is that it
lumps all of the data together because the therapy is the same or
very similar. However, this study grouped together the following
therapies from 14 studies that have little to do with each
other:

  • Cultured expanded bone marrow MSCs
  • Culture-expanded adipose MSCs
  • Stromal Vascular Fraction (SVF)
  • Culture expanded placental MSCs
  • Culture expanded umbilical cord MSCs
  • Bone Marrow Concentrate (BMC) with PPP

Just going over why these therapies are vastly different and
can’t scientifically be aggregated will teach a tremendous amount
about stem cells. The differences can be broken down into three
main categories:

  • Processed Cell Mixtures
  • Cultured Expanded and Isolated Cells
  • Different Cell Sources

Let’s now analyze why these treatments are HUGELY
DIFFERENT.

Processed Cell Mixtures

Two of the therapies above contain mixtures of lots of cells
where the minority of those cells are “mesenchymal stem cellsâ€.
These are SVF and BMC. These are dramatically different in many
ways.

SVF is created by digesting fat tissue to break down the
structural collagen and then centrifuging out the cells. What you
get is a mixture of different white blood cells, red blood cells,
macrophages, hematopoietic stem cells, other cells, and some
mesenchymal stem cells (2).

Bone marrow concentrate is created by taking bone marrow
aspirate (the liquid portion of the bone marrow) and centrifuging
it to isolate the buffy coat. That contains a mixture of different
white blood cells, red blood cells, macrophages, hematopoietic stem
cells, other stem cells, progenitor cells, and some mesenchymal
stem cells (5).

First, the percentage of mesenchymal stem cells differs between
these two. While fat has more of these, the MSCs in the bone marrow
are more efficient at cartilage repair (6-18). Second, there are
vast differences in the non stem cell components of these mixtures.
For example, while SVF is poor in hematopoietic stem cells (HSCs),
bone marrow is rich in these cells. So in the end, these cell
mixtures are as different as two different drugs (19,20).

In addition, if we just took one of these mixtures and tried to
compare just that type across different bedside machines there
would also be vast differences. For example, a study I performed
with a Stanford researcher several years back found huge
differences between different BMC mixes used in clinical practice
(5).

Cultured Expanded and Isolated Cells

If the above therapies are a mix of different cells, this
category is the opposite. Here, the above products of tissue
digestion and centrifugation are then plated in tissue culture to
isolate only the adherent MSCs. This is then repeated multiple
times until you get a “pureish†mixture of cells that are
called MSCs.

We still have the same problems as above, as the adipose MSCs
will perform differently than the bone marrow cells which will
perform differently than the placental cells which will perform
differently than the umbilical cord cells (3, 4, 21-23). In fact,
how you grow these cells will also change their final properties on
the body. For example, were they grown in a culture media that’s
from a different animal? (24) The same animal? The same patient or
a different patient? With exogenous growth factors or not? All of
these choices produce different cell lines (25, 26).

Different Cell Sources

As I alluded to above, we have four different cell sources
here:

  • Adipose
  • Bone marrow
  • Placenta
  • Umbilical cord

At best these MSCs are distant kissing cousins rather than
identical twins. For example, if we take the ability of these cells
to suppress inflammation, they are all massively different. There
are also other cell properties that make these cells for all
intents and purposes, different therapeutics (27-32).

A Meta-Analysis of Different Therapies?

Pooling data on a specific therapy from different studies
obviously requires that the therapy is the same. Given that these
authors looked at 14 studies that used six very different
therapies, the paper falls apart at it’s most basic critique.
Meaning that it isn’t a meta-analysis and the data can’t be
pooled or even compared head to head.

How Did this Paper Get Published?

Arthroscopy is a high impact factor orthopedic journal. Did the
reviewers not understand that these were VERY different therapies?
Could they be that oblivious to what’s published in the
literature?

This brings me back to my initial thoughts. The publication of
research is often very political. Does one side or another of an
issue want the message to get out there and are they willing to
overlook a few nasty warts to get the message published? In this
case, this paper fails at being able to support its most basic
structural concepts, yet somehow it got greenlighted in a major
journal.

The upshot? This paper is a mess of gargantuan proportions.
I’ve covered only one issue here, but tomorrow I’ll uncover
many more. Hence, this article doesn’t actually show that these
therapies are ineffective. In fact, tomorrow, I’ll show you how
the paper actually shows the opposite.

_________________________________

References

(1) Dai W, Leng X, Wang J, Shi Z, Cheng J, Hu X, Ao Y.
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