Marc Darrow MD,JD

One of the questions that is often asked is whether or not the native stem cells in knees are still working or are they too old to work?

Research has shown that native stem cells do continue to try to heal knee damage. The addition of stem cells to the knee can help them work more efficiently and more productively. Let’s look at research.

In 2011, doctors at the University of Aberdeen published research in the journal Arthritis and rheumatism that provided the first evidence that resident stem cells in the knee joint synovium underwent proliferation (multiplied) and chondrogenic differentiation (made themselves into cartilage cells) following injury.(1)

This paper, presenting the idea that stem cells in an injured knee increased in numbers in preparation of healing, has been cited by more than 52 medical studies. If the stem cells in your knee synovial lining are abundant and could rebuild cartilage after injury, why isn’t your knee fixing itself?

“If the stem cells in the knee synovial lining are abundant and have the ability to rebuild cartilage after injury, why isn’t the knee fixing itself?”

One of those 52 medical studies I just mentioned, was performed by researchers at the University of Calgary in 2012. Among their questions, was the same question we just speculated on: “If the stem cells in the knee synovial lining are abundant and have the ability to rebuild cartilage after injury, why isn’t the knee fixing itself?” Here is what they published in the medical journal PLOS ONE.(2)

“Since osteoarthritis leads to a progressive loss of cartilage and synovial progenitors (rebuilding) cells have the potential to contribute to articular cartilage repair, the inability of osteoarthritis synovial fluid Mesenchymal progenitor cells (stem cell growth factors) to spontaneously differentiate into chondrocytes suggests that cell-to-cell aggregation and/or communication may be impaired in osteoarthritis and somehow dampen the normal mechanism of chondrocyte replenishment from the synovium or synovial fluid. Should the cells of the synovium or synovial fluid be a reservoir of stem cells for normal articular cartilage maintenance and repair, these endogenous sources of chondro-biased cells would be a fundamental and new strategy for treating osteoarthritis and cartilage injury if this loss of aggregation and differentiation phenotype can be overcome.”

In common terms, the “reservoir of stem cells for normal articular cartilage maintenance and repair,” already in the knee, are not fixing the knee because of a confused communication. The joint environment has changed from healing to degenerative and made clear communications “murky.” This is attested to in the research by this concluding statement:

“These results reveal a fundamental shift in the chondrogenic ability of cells isolated from arthritic joint fluids, and we speculate that the mechanism behind this change of cell behavior is exposure to the altered milieu of the osteoarthritis joint fluid.”

The paper suggests that getting these stem cells communicating and healing would create a fundamental new strategy in healing. Umbilical cord blood stem cell therapy helps with this problem of communication as demonstrated in the above studies.

This research was supported in a study from December 2017 published in the journal Nature reviews. (3) The paper suggested that recognizing that joint-resident stem cells are comparatively abundant in the joint and occupy multiple niches (from the center of the joint to the outer edges) will enable the optimization of single-stage therapeutic interventions for osteoarthritis.

Growth factors bring blood and healing factors to the degenerative damage

You need blood circulation for healing – growth factors make new blood highways

From my early start in regenerative medicine until now, the role of inflammation in healing and the need to bring circulation to a degenerated joint has not changed. To heal a bad knee, a bad hip, a bad shoulder, to heal anything, you need blood circulation and the healing and growth factors blood brings to the site of injury and degeneration. These are the amazing things blood does:

  • Blood brings healing elements to the site of joint damage
  • Blood takes away diseased tissue from that site.
  • Blood also brings oxygen that helps create an “anti-oxidant” healthy joint environment and takes away the “oxidant” toxic sludge that develops as a byproduct of chronic inflammation in the joint’s synovial tissue.

Above we discussed stem cell therapy could change a diseased joint environment into a healing joint environment.

To get blood to an injury you need new blood vessels

Angiogenesis is the scientific term to describe the process of creating new blood vessels, “Angio” meaning related to blood vessels, “Genesis,” the creation of new blood vessels are formed as new branches of existing blood vessels. One of the growth factors found in human umbilical cord blood is called ANG-1.

ANG-1

ANG-1 is an Angiopoietin. Angiopoietins are protein growth factors in a developing baby that helps with vascular development and the formation of the blood circulatory network. When this growth factor is introduced into a degenerative joint it starts talking to the endothelium tissue cells that line the patient’s blood vessels.

What do they talk about?

It works together with the surrounding cellular matrix (the growth factors already in your body that surround your stem cells) and mesenchyme, the cells of the connective tissue, and your mesenchymal stem cells. ANG-1 also talks to your lymphatic vessels to prepare them for an increased flow of toxins and damaged tissue, that will be coming out of your joint.

Basic Fibroblast Growth Factor (bFGF)

Another important growth factor found in the blood and stem cells are called basic fibroblast growth factor (bFGF). bFGF does many things, but in the context of this article, let’s focus on bFGF’s activity during injury repair.

  • bFGF helps with the formation of new blood vessels in conjunction with ANG-1.
  • bFGF lives in the subendothelial extracellular matrix of blood vessels, the growth factor pool of stem cells in the blood vessel lining. Here it helps move oxygen and nutrients to support the cells healing damaged tissue and it helps with the sprouting of new blood vessels during angiogenesis.

Vascular Endothelial Growth Factor (VEGF)

As its name implies, Vascular Endothelial Growth Factor (VEGF) is involved in vascular and blood vessel cell development. VEGF makes blood vessels that helps form new bone and cartilage.

  • Blood flow assists bone and cartilage

Now let’s watch the interplay between these growth factors in the development of new bone and cartilage.

  • Basic fibroblast growth factor (bFGF) is involved with the differentiating of mesenchymal stem cells into osteoblasts, bone cells.
  • Vascular Endothelial Growth Factor (VEGF) makes bone from cartilage cells.
  • In a developing baby, growth plates are soft areas at the end of long bones. The area remains soft through puberty or until the adolescent reaches a state of maturation and growing has stopped.
  • At this point, the soft, flexible cartilage-like growth plate turns into bone. A constant state of blood flow is needed for this new and developing bone. VEGF makes sure it is there.

So now you understand how this works in a baby and a developing adolescent, but, how does this work in the aging population and their challenges of degenerative disease? Researchers at Harvard give this recap in the medical journal Bone: (4)

  • “VEGF is one of the most important growth factors for regulation of vascular development and angiogenesis. Since bone is a highly vascularized organ (abundant blood circulation) and angiogenesis plays an important role in osteogenesis (formation of bone) VEGF also influences skeletal development and postnatal bone repair.
  • Compromised bone repair and regeneration in many patients can be attributed to impaired blood supply; thus, modulation of VEGF levels in bones represents a potential strategy for treating compromised bone repair and improving bone regeneration.
  • Local administration of VEGF may be useful in treatment of impaired bone healing/regeneration as a consequence of age or osteoporosis.” In other words, bring blood to the damaged bone.

You need cellular communication for healing – growth factors make new communication networks that send signals to grow bone

Above, I touched on cell signaling, and that  stem cells start conversations with the cells in an already damaged joint.

Basic fibroblast growth factor (bFGF) in addition to its role as a growth factor, is a signaling protein. Signaling proteins help cells communicate with each other and provide navigational signals. Navigation is obviously an important element in healing, in that healing cells need to know where they are going to in the damaged joint.

Transforming growth factor-beta (TGF-β)

Transforming growth factor-beta (TGF-β) found in umbilical cord blood is a growth factor of great interest in bone healing. What makes it so interesting is that it stimulates your own stem cells to reboot the healing process. How? By way of communicating with the other cells.

In January 2019 researchers examined the role of growth factors in helping stem cells in a damaged joint get to the point of injury. The study published in the journal Biochemical and biophysical research communications (5) found that “Endogenous (your own) bone marrow-derived mesenchymal stem cells are mobilized into peripheral blood and injured tissues by various growth factors and cytokines (messenger cells) that are expressed in the injured tissues, such as transforming growth factor-beta (TGF-β).”

In the research above, we see that stem cell growth factors help the damaged healing communication system in degenerative joints reset and restart. In doing so, the healing communications network starts giving commands to the cells to start healing again.

Here is some interesting research from doctors in the United Kingdom published in the November 2017 issue of Future science OA (19). The study from the University of Leeds and Leeds Teaching Hospital discusses native stem cell activity in degenerative knee disease.

The researchers found signs of tissue adaptation and attempted repair responses in osteoarthritis-affected osteochondral (bone and cartilage) tissues. What this means is that even in advanced osteoarthritis, the knee (and the stem cells within it) is trying to heal itself. But it is an attempted repair that never completes. So now the focus shifts to what can doctors do to help the stem cells complete the repair. One answer is more communicating growth factors from native and injected stem cells.

Do you have questions about your treatment options? Ask Dr. Darrow

Marc Darrow, MD. JD., discusses the treatment philosophy of the Darrow Stem Cell Institute. Transcript of video

A leading provider of stem cell therapy, platelet rich plasma and prolotherapy
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References:

1 Kurth TB, Dell’accio F, Crouch V, Augello A, Sharpe PT, De Bari C. Functional mesenchymal stem cell niches in adult mouse knee joint synovium in vivo. Arthritis Rheum. 2011 May;63(5):1289-300. doi: 10.1002/art.30234.
2 Krawetz RJ, Wu YE, Martin L, Rattner JB, Matyas JR, Hart DA. Synovial Fluid Progenitors Expressing CD90+ from Normal but Not Osteoarthritic Joints Undergo Chondrogenic Differentiation without Micro-Mass Culture. Kerkis I, ed. PLoS ONE. 2012;7(8):e43616. doi:10.1371/journal.pone.0043616.
3 McGonagle D, Baboolal TG, Jones E. Native joint-resident mesenchymal stem cells for cartilage repair in osteoarthritis. Nature Reviews Rheumatology. 2017 Dec;13(12):719.
4 Hu K, Olsen BR. The roles of vascular endothelial growth factor in bone repair and regeneration. Bone. 2016;91:30-8.
5 Yu J, Kim HM, Kim KP, Son Y, Kim MS, Park KS. Ceramide kinase regulates the migration of bone marrow-derived mesenchymal stem cells. Biochemical and biophysical research communications. 2019 Jan 8;508(2):361-7. / 1169

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