Induced Pluripotent Stem Cell-Derived Kidney Progenitor Cells Heal Kidneys in Laboratory Animals


The kidney is a crucial organ for human survival and human flourishing. This organ filters metabolic wastes from the blood and if the kidney does not work, the body slowly poisons itself.

When the kidneys fail to work properly, they must be replaced by transplantation of a tissue-matched kidney from a donor. However, if the kidney is not completely damaged, then it might be possible to heal it by means of cell therapies. For example, if we could transplant renal progenitor cells into the kidney that then differentiate into kidney-specific tissues, then we could potentially replace damaged tissues in the kidney and help the kidney fully recover. The tough part of such a treatment strategy has been acquiring a sufficient number of kidney progenitor cells. However, scientists have considered using induced pluripotent stem cells (iPSCs), since these cells can be expanded in culture to very high numbers of cells that can be effectively differentiated into kidney progenitors.

Induced pluripotent stem cells are made from mature, adult cells by means of a combination of genetic engineering and cell culture techniques. These cells have the potency to differentiate into any cell type in the human body. Ideally, renal progenitors could be transplanted directly into the kidney parenchyma, but, again, this is not a simple-to-solve problem. “The kidney is a very solid organ, which makes it very difficult to bring enough number of cells upon transplantation,” explains Professor Kenji Osafune. Dr. Osafune’s laboratory is at the Center for iPS Cell Research and Application (CiRA) at Kyoto University, Japan, and is using iPSCs to investigate new treatments for kidney disease. Several studies have successfully transplanted adequate numbers of kidney progenitors to treat kidney disease.

In a new study, Dr. Osafune has collaborated with Astellas Pharma Inc., in order to potentially design a solution that can solve the problem of treating the kidney with exogenous cells. In this study, Osafune and his colleagues tried a different way to deliver the kidney progenitor cells. Instead of injecting cells directly into the kidney, they transplanted their iPSC-derived renal progenitors into the kidney subcapsule that is at the kidney surface.

Kidney Capsule

The mice that received the cells were suffering from acute kidney injury. Even though the transplanted cells never integrated with the host, mice that received this transplant showed better recovery, including less cell death (necrosis) and scarring (fibrosis) compared with mice that received transplants of other cell types.

Damaged kidney tissue (left) of an AKI model mouse shows high levels of fibrosis (blue). Treatment with Osr1+Six2+ cell therapy significantly ameliorates the fibrosis (right) of another AKI model mouse.
Damaged kidney tissue (left) of an AKI model mouse shows high levels of fibrosis (blue). Treatment with Osr1+Six2+ cell therapy significantly ameliorates the fibrosis (right) of another AKI model mouse.

Osafune attributed the improvement in his laboratory mice to the use of cells that expressed the Osr1 and Six2 genes. The Osr1 and Six2 proteins are known markers of renal progenitor cells, but until this particular study, researchers had not exclusively used cells that expressed both of these proteins for cell therapies.

Kidney Progenitor cells

Another conclusion from the study was that because the cells did not integrate into the kidney, their therapeutic effects were the result of secreted proteins that promoted kidney healing and protection. While most stem cell therapies aim for integration of the transplanted cells, the results of these experiments could have important clinical implications. In particular, this experiment is one of the first to show the benefits of using human iPS cell-derived renal lineage cells for cell therapy. Secondly, scarring of the kidney is a marker that indicated progression of the kidney to chronic kidney disease. Since scarring was significantly reduced in these experiments, these data suggest that the paracrine effects of the transplanted cells could act as preventative therapy for other serious ailments. Finally, Osafune believes these effects could provide valuable clues for drug discovery. “There is no medication for acute kidney injury. If we can identify the paracrine factor, maybe it will lead to a drug.”

From:  Takafumi Toyohara, et al., “Cell therapy using human induced pluripotent stem cell-derived renal progenitors ameliorates acute kidney injury in mice” Stem Cells Translational Medicine.

Wound Healing and Human Umbilical Cord Mesenchymal Stem Cells


Previous studies have shown that human bone marrow–derived mesenchymal stromal cells have potential to accelerate and augment wound healing. However, in the clinic, it is difficult to properly culture and then use bone marrow stem cells. Human umbilical cord blood–derived mesenchymal stromal cells (hUCB-MSCs) recently have been commercialized for cartilage repair as a cell-based therapy product that uses allogeneic stem cells.

Presently, current cell therapy products for wound healing utilize fibroblasts. Is it possible that hUCB-MSCs are superior to fibroblasts for wound healing? Seung-Kyu Han and his colleagues from the Department of Plastic Surgery at the Korea University College of Medicine in Seoul, South Korea used a cell culture system to compare the ability of hUCB-MSCs and fibroblasts to heal wounds.

For their study, Han and others used diabetic mice and isolated fibroblasts from normal and diabetic mice. Then they tested the ability of these cells to heal skin wounds in the very mice from which they were isolated. A third group of diabetic mice with skin wounds were treated with hUCB-MSCs. A comparison of all three groups examined the cell proliferation, collagen synthesis and growth factor (basic fibroblast growth factor, vascular endothelial growth factor and transforming growth factor-β) production and compared them among the three groups.

The results showed that hUCB-MSCs produced significantly higher amounts of vascular endothelial growth factor and basic fibroblast growth factor in comparison to both fibroblast groups. Human UCB-MSCs were better than diabetic fibroblasts but healthy fibroblasts in collagen synthesis, and there were no significant differences in cell proliferation and transforming growth factor-β production. Human UCB-MSCs produced significantly higher amounts of VEGF and bFGF when compared with both fibroblasts.

These results suggest that Human UCB-MSCs might be a better source for diabetic wound healing than either allogeneic or autologous fibroblasts. Larger animal studies will be needed, but this particular study seems like a good start.

Adding Cyclosporin to Bone Marrow Might Increase Stem Cell Numbers, Quality, and Engraftment Efficiency


In the bone marrow, we have an army of blood cell-making stem cells called hematopoietic stem cells (HSCs) that make all the blood cells that course through our blood vessels. These cells divide throughout our lifetimes, and they replacement themselves while they generate all the red and white cells found in our blood.

hematopoietic-stem-jpg

HSCs are also the cells that are harvested during bone marrow aspirations and biopsies. Transplantation of HSCs can save the lives of patients with blood cancers or other types of blood-or bone marrow-based diseased.

Harvesting and transplanting HSCs is, therefore, a very important clinical strategy for treating many different types of blood disorders and diseases. However, this crucial strategy is limited by the relative rarity of HSCs in isolated bone marrow. Additionally, the number and function of HSCs deteriorate both during their collection from the bone marrow (BM) and during their manipulation outside the body. Fortunately, the development of culture conditions that best mimic the environment these cells experience in bone marrow (the so-called “HSC niche environment”) may help to minimize this loss.

Scanning electron microscopy of stem cells (yellow / green) in a scaffold structure (blue) serving as a basis for the artificial bone marrow.
Scanning electron microscopy of stem cells (yellow / green) in a scaffold structure (blue) serving as a basis for the artificial bone marrow.

One of the most important variables for HSC viability is oxygen concentration, since various studies have shown that the oxygen concentrations found in ambient air seems to be damaging to HSCs, which normally are found in rather oxygen-poor reaches in bone marrow. Researchers from the laboratory of Hal Broxmeyer at the Indiana University School of Medicine have discovered that HSCs suffer from ‘‘extra-physiologic oxygen shock/stress (EPHOSS)” if they are harvested under ambient oxygen conditions. On top of that, treatment of the collected HSCs with the immunosuppressant drug cyclosporin A (CSA) can inhibit this stress, enhance the yield of collected HSCs, and increase their transplantation efficiency.

When Broxmeyer and his colleagues compared mouse BM that had been harvested under normal oxygen concentrations (21% O2) and low-oxygen concentrations (3% O2), they observed that the hypoxic (low-oxygen) treatment caused a 5-fold increase in the number of Long Term (LT) self-renewing HSCs, and a decrease in harmful reactive oxygen species (ROS) and mitochondrial activity. Broxmeyer and others also confirmed the positive effect of hypoxia on HSC collection from human cord blood. When mouse BM collected under different conditions were assayed by competitive transplantation, the “hypoxic HSCs” engrafted more efficiently in recipient mice. This increased engraftment was not due to enhanced homing or reduced cell death. Instead it seems that the stress response to non-physiological oxygen concentrations (EPHOSS) has a rapid and significant damaging effect in HSCs.

Broxmeyer decided to take this study one step further. In mitochondria (the powerhouse of the cell), increased expression of the mitochondrial permeability transition pore (MPTP) seems to be one of the key mechanism by which oxidative stress affects HSCs.

mitochondrial permeability transition pore
mitochondrial permeability transition pore

Induction of the MPTP leads to mitochondrial swelling and uncoupled energy production (which leads to the generation of reactive oxygen species, otherwise known as “free radicals). This leads to cell death apoptosis and necrosis, and intermittent MPTP activation may also decrease stem cell function in general without killing the cells. Broxmeyer and his coworkers came upon a rather ingenious idea to use the drug cyclosporin A (CSA) to antagonize MPTP induction, since CSA inhibits the associated CypD (cyclophilin) protein. When HSCs were collected under high-oxygen conditions in the presence of CSA, there was a 4-fold increase in the recovery of LT-HSCs and enhanced engraftment levels compared to HSCs harvested in high-oxygen conditions without CSA. This link was further strengthened by examining the HSCs of mice with a deletion of the CypD gene. In these mice, HSCs collected under high-oxygen conditions showed increased LT-HSC recovery and decreased LT-HSC ROS levels compared to wild-type mice.

Cyclophilin
Cyclophilin

How, harvesting and processing HSCs from bone marrow in a low-oxygen environment within a transplant clinic is generally not possible. However, given the observed advantages, the application of CSA may represent an easy and attractive alternative. The authors of this paper (which was published in the journal Cell) note that CSA is already used in the clinic as an immunosuppressant. Therefore, this technique could potentially be rapidly adapted into bone marrow harvesting techniques.

An additional thought is that studies that use other types of stem cells for transplantation might also need to consider the effects of EPHOSS and oxygen concentration while preparing their cells in other model systems.

See “Enhancing Hematopoietic Stem Cell Transplantation Efficacy by Mitigating Oxygen Shock” from Cell by Stuart P. Atkinson

Mesoblast MPCs Improve Heart Function in Patients with Congestive Heart Failure


Mesoblast Limited is a biotechology company with a singular interest in developing cell-based, regenerative therapies to treat some rather common, but severe ailments. Mesoblast has a proprietary cell system based on specialized cells known as mesenchymal lineage adult stem cells. These mesenchymal lineage adult stem cells (MLASCs) are being designed to serve as ‘off-the-shelf’ cell products for treating heart conditions, orthopedic disorders, immunologic/inflammatory disorders and cancer.

Mesoblast has recently released the results of a Phase 2 clinical trial that utilized their therapeutic product MPC-150-IM and tested it in patients with chronic congestive heart failure. The results of this study were published in the journal Circulation Research, a high-impact journal of the American Heart Association.

Patients who suffer from advanced heart failure have a poor long-term prognosis and they also have few therapeutic options. The pumping power of their hearts is weaker than normal, and the blood moves through the heart and body at a slower than normal rate. Consequently, fluid pressure in the heart increases and the chambers of the heart respond by stretching to hold more blood to pump through the body or by thickening and becoming stiff. This helps to keep the blood moving, but the heart muscle walls may eventually weaken and become unable to pump as efficiently. The kidneys respond by causing the body to retain fluid (water) and salt, and if the fluid builds up in the arms, legs, ankles, feet, lungs, or other organs, the body becomes congested, and congestive heart failure is the term used to describe the condition.

Mesoblast decided to test their proprietary Mesenchymal Precursor Cells (MPCs) to potentially induce heart muscle repair, stimulate new blood vessel growth, decrease cell death and reduce scar formation. Earlier studies established that MPCs are safe to give to heart patients. This new study examined the ability of these cells to improve heart function in patients with congestive heart failure.

In this study, 60-patients were subjected to a blinded, placebo-controlled trial. MPCs were injected directly into the heart muscle. One of the Primary Endpoints of this study was safety.

Patients included those with ischemic or non-ischemic heart failure (due to left ventricular systolic dysfunction), and in both groups, MPC injections were feasible and safe. There was a similar incidence of adverse events across all control and treatment groups. The patients who were treated with MPCs did not show any clinically significant immune response again the injected MPCs.

When it came to the main Secondary Efficacy Endpoints, patients who were treated with the highest MPC dose showed the greatest improvement in left ventricular remodeling compared to controls as evidenced by significant reductions in Left Ventricular End Systolic Volume (LVESV; p=0.015), and Left Ventricular End Diastolic Volume (LVEDV; p=0.02), 6 months after the treatment. LVESV and LVEDV increase as the heart gets weaker, but in these patients, the LVESV and LVEDV decreased. There were also parallel improvements in ejection fraction, but these improvements were not statistically significant. Patients treated with the highest dose of MPCs also showed the greatest improvement in functional exercise capacity compared to controls (p=0.062) 12 months after receiving their treatments.

Finally, in a post-hoc analysis of all patients 36 months after treatment, patients treated with MPCs showed significantly lower incidence of major adverse cardiac events when compared to the control group (0% vs 33% HF-MACE by Kaplan-Meier, p=0.026 by log-rank).

In their article, entitled ‘A Phase II Dose-Escalation Study of Allogeneic Mesenchymal Precursor Cells in Patients With Ischemic or Non-Ischemic Heart Failure’, the authors concluded that high-dose MPC treatment seems to reduce heart failure-related major adverse cardiovascular events and provide beneficial effects on adverse left ventricular remodeling.

Lead author and investigator Dr Emerson C. Perin, Director, Research in Cardiovascular Medicine and Medical Director of the Stem Cell Center at the Texas Heart Institute, said: “The findings from this trial are very encouraging and suggest that a high-dose of Mesoblast’s allogeneic cell-based therapy may decrease major clinical events associated with progressive heart failure for at least three years, including repeated hospitalizations or death.

“These effects appear to be due to the ability of these cells to positively impact on adverse cardiac remodeling associated with chronic heart failure. If these results are confirmed in the ongoing Phase 3 trial currently recruiting at our institution and elsewhere, this new therapy has the potential to change the paradigm for the management of patients with advanced heart failure and a high risk of hospitalization and death,” Dr Perin added.

A randomized, placebo-controlled Phase 3 trial using Mesoblast’s high-dose MPC 150M is being conducted by Mesoblast’s development and its commercial partner, Teva Pharmaceutical Industries Ltd. Presently, this study is actively enrolling patients across multiple clinical sites in North America.

Defending Planned Parenthood with Medical Language


The possibility that an organization like Planned Parenthood is selling fetal tissue procured from the dismembering of unborn children is deeply troubling.  However, some of the statements offered by defenders of Planned Parenthood are quite revealing.

In the New Republic, Dr. Jen Gunter, an OB/GYN makes the following statements:  “These are not ‘baby parts.’ Whether a woman has a miscarriage or an abortion, the tissue specimen is called “products of conception.”  This is pure rubbish.  Unborn babies are still babies whether you want to call them that or not.  Parts of their bodies are therefore baby parts.  I will grant that these are fetal baby parts, but they are baby parts all the same.  If they were not, then why would biotechnology companies or university research laboratories find them so valuable?  Because they are cells, tissues, and organs from unborn babies.  A very young human embryo results from conception (or the completion of fertilization), and this young embryo represents the earliest stages in the life of a human person.  “Products of conception” is a general term to describe the bodies of unborn after they die either by natural or unnatural means.    The term says nothing about how the unborn baby died, when they died, or why they died.  Likewise when an adult dies their body is called a “cadaver.”  The term says nothing about how the individual died, and neither does it reduce the humanity of the person who just died.  Therefore what we call an unborn baby’s lifeless body does not detract from the fact that this unborn baby in the fetal or embryonic stage of development is a young, unborn human person and, yes, a baby, albeit one who has yet to be born.

Dr. Gunter continues:  “The term baby is medically incorrect as it doesn’t apply until birth. Calling the tissue “baby parts” is a calculated attempt to anthropomorphize an embryo or fetus. It is a false image—a ten to twelve week fetus looks nothing like a term baby—and is medically incorrect.”  If the term “baby” is medically incorrect, then why did the documentary “Twice Born” about fetal surgery refer to this procedure as surgery on an “unborn baby.”  This is not anthropomorphizing unborn babies.  Look at the picture below of a ten-week-old baby and tell me that this unborn child does not look like a human baby.  Despite her incipient state, she is clearly a very young human baby at this stage.

10-week-fetus

There is nothing false about this image.  When we end the life of a ten-week-old baby like this one we are killing an unborn baby.  All the defining it out of existence and medicalese will not change that.

“Hearing medical professionals talk casually about products of conception may seem distasteful to some, but not to doctors. Medical procedures are gory by nature.”  She then goes on to discuss medical procedures that include surgery.  The procedures described are designed to save lives and not end them.  We find the cavalier discussion of the trafficking of baby parts distasteful because it results from the physical dismembering of the weakest and most vulnerable members of the medical community.  To place abortion alongside life-saving procedures like cutting out cancers or dealing with broken limbs is a non sequitur of the first order.

Then she claims that “FactCheck.org contacted several researchers who work with human tissue, and the price range mentioned in the videos—$30 to $100 per patient—is on the low-end. ‘There’s no way there’s a profit at that price,’ Sherilyn J. Sawyer, the director of Harvard University and Brigham and Women’s Hospital’s Biorepository, told the website.”  Since Dr. Sawyer does not run an abortion clinic, how would she know?  I will grant that she knows about compiling with federal law when it comes to the procurement of fetal tissue, but how would she know how much it costs the clinics?  If the companies or tissue repositories are coming into the clinics and taking the tissue straight after the procedures are performed, as mentioned in the videos, what expenses are incurred besides paperwork costs?  If the tissue is shipped there are shipping costs, but those are paid by the company.  In these videos, there was no talk of covering administrative costs, which is allowed by law.  Instead there was talk of prices for fetal tissue for the clinics for the sake of profit and that is illegal (see statute above).  How would we know if the clinics are making a profit off this unless they are investigated?  Dr Gent’s entire argument is irrelevant and a dodge.

Finally, Dr. Gent equates those who are troubled by these videos with those who deny the moon landings.  This is ridiculous and is the sign of a failed, desperate argument.  She writes, “there are those who refuse to believe that the full scope of reproductive health care is grounded in medical evidence.”  Well the medical evidence shows that abortion ends the life of the youngest members of the human community who are at their weakest and most vulnerable simply because, in the vast majority of the cases, they have the misfortune of being an inconvenience.  Equating those of us with the sense to see that with people who deny the moon landing is risible.

Hopefully Congress will do what they need to do and the Justice Department will do what they should do, but in this highly politicized administration, I would not hold my breath.

Planned Parenthood and Fetal Tissue Procurement


Unless you have been without any internet access for the past month or so, you have probably heard about the undercover videos made by David Daleiden of the Center for Medical Progress that feature the chief medical director of Planned Parenthood, Dr. Deborah Nucatola,  discussing the sale of fetal tissue that results from an abortion, and Dr. Mary Gatter, the Medical Directors’ Council President for Planted Parenthood doing essentially the same thing.

The emotional impact of these videos are immense, but I would like to try to step back from that and discuss the legal side of these videos.  Fetal tissue procurement is heavily regulated by the Federal government.  The specific laws that regulate human fetal tissue procurement are shown below:

42 U.S. Code § 289g–2 – Prohibitions regarding human fetal tissue
a) Purchase of tissue
It shall be unlawful for any person to knowingly acquire, receive, or otherwise transfer any human fetal tissue for valuable consideration if the transfer affects interstate commerce.
(b) Solicitation or acceptance of tissue as directed donation for use in transplantation
It shall be unlawful for any person to solicit or knowingly acquire, receive, or accept a donation of human fetal tissue for the purpose of transplantation of such tissue into another person if the donation affects interstate commerce, the tissue will be or is obtained pursuant to an induced abortion, and—
(1) the donation will be or is made pursuant to a promise to the donating individual that the donated tissue will be transplanted into a recipient specified by such individual;
(2) the donated tissue will be transplanted into a relative of the donating individual; or
(3) the person who solicits or knowingly acquires, receives, or accepts the donation has provided valuable consideration for the costs associated with such abortion.
(c) Solicitation or acceptance of tissue from fetuses gestated for research purposes
It shall be unlawful for any person or entity involved or engaged in interstate commerce to—
(1) solicit or knowingly acquire, receive, or accept a donation of human fetal tissue knowing that a human pregnancy was deliberately initiated to provide such tissue; or
(2) knowingly acquire, receive, or accept tissue or cells obtained from a human embryo or fetus that was gestated in the uterus of a nonhuman animal.
(d) Criminal penalties for violations
(1) In general
Any person who violates subsection (a), (b), or (c) shall be fined in accordance with title 18, subject to paragraph (2), or imprisoned for not more than 10 years, or both.
(2) Penalties applicable to persons receiving consideration
With respect to the imposition of a fine under paragraph (1), if the person involved violates subsection (a) or (b)(3), a fine shall be imposed in an amount not less than twice the amount of the valuable consideration received.
(e) Definitions
For purposes of this section:
(1) The term “human fetal tissue” has the meaning given such term in section 289g–1 (g) of this title.
(2) The term “interstate commerce” has the meaning given such term in section 321 (b) of title 21.
(3) The term “valuable consideration” does not include reasonable payments associated with the transportation, implantation, processing, preservation, quality control, or storage of human fetal tissue.

If we wade through the legalese, we can see that you cannot sell fetal tissue.  It has to be donated and it cannot come from a pregnancy whose sole purpose was to provide a source of fetal tissue.  You may not sell it for a profit.  You may also not transplant it.  All of this is meant to prevent women from having babies so they can sell their parts for money.  For this reason, abortion clinics may not use the possibility of fetal tissue donation as an inducement to persuade women to have an abortion.

In both of these videos, Planned Parenthood executives, not people who run individual centers, medical directors, which makes this official Planned Parenthood policy, actively discuss the prices of fetal organs.  That reflects an intent to sell fetal organs and that means that these videos reflect an intent to break a Federal law.  If this reflects routine Planned Parenthood policy and/or practice, then they are routinely breaking the law.

As you can see, at the very least, this deserves an investigation.  If Planned Parenthood clinics routinely charge biotechnology companies beyond their normal administrative and medical costs for fetal tissue, then they are breaking the law.  Maybe that is not the case (I highly doubt it frankly, but that’s my take), but we do not know without an investigation.  The Justice Department should become involved quickly and all federal funding of Planned Parenthood should be suspended pending full cooperation with a Federal investigation.  This should be the minimal results of these troubling videos.

Genetically Engineered Stem Cells to Treat Osteoporosis in Mice


Osteoporosis is a nasty condition characterized by weak and brittle bones often leading to devastating bone fractures and other injuries. Unfortunately, millions of people worldwide have been diagnosed with osteoporosis.

Osteoporosis

Contrary to popular belief, out bones are dynamic organs that undergo constant remodeling consisting of bone resorption and renewal. However, once bone resorption rates outpace bone renewal, bone densities decrease, which puts bones at risk of fractures. Medical researchers are would like to find new ways to not only discourage bone resorption, but generate new bone material to replace demineralized bone. Ideally, therapies would rejuvenate bone growth so that it the bone reverts back to its original density levels.

Now a promising strategy to accomplish this goal is relies on stem cell therapy. A collaborative study by Xiao-Bing Zhang and his colleagues from Loma Linda University and Jerry L. Pettis from the Memorial VA Medical Center has built on their prior work with genetically modified hematopoietic stem cells (HSCs) that identified a growth factor that caused a 45% increase in bone strength in mouse models. This work was published in the journal Proceedings of the National Academy of Sciences, USA.

Zhang and his coworkers wanted to find a gene therapy that promotes bone growth while minimizing side effects. To that end, Zhang’s group focused on a growth factor called PGDFB or “platelet-derived growth factor, subunit B.” The properties of this growth factor make it a promising candidate, since it is already FDA approved for treating bone defects in the jaw and mouth.

platelet-derived growth factor, subunit B
platelet-derived growth factor, subunit B

First, Zhang and others isolated HSCs from the bone marrow of donor mice. HSCs were chosen because they can be given intravenously, after which they will home in to one of the major sites of bone loss (the endosteal bone surface). The isolated HSCs were then genetically engineered to overexpress the growth factor PGDFB. Experimental mice were then irradiated to wipe out their own HSCs, and then these same mice were transplanted with the modified HSCs.

After four weeks, the upper leg bones of the mice (femur) were tested. Zhang and his colleagues found that PGDFB promoted new trabecular bone formation, but because the PGDFB was expressed at high levels, it negatively affected bone mineral density. Zhang and others then used weaker promoters to optimize the dosage of PGDFB expression in the HSCs. They discovered that the phosphoglycerate kinase promoter (PGK) worked well to mitigate the amount of PGDFB that is expressed in cells. When these HSCs were transplanted into irradiated mice, they observed increases in trabecular bone volume, thickness, and number as well as increases in connectivity density. Additionally, cortical bone volume increased by 20-30% while cortical porosity was reduced by 40%. Importantly, the lower dosage of PGDFB resulted in no observed decreases in bone mineral density due to osteomalacia or hyperparathyroidism.

These treated femurs and a control sample underwent three-point mechanical testing to test the integrity of the new bone. The PGK-PGDFB-treated femur displayed a 45% increase in maximum load-to-failure in the midshaft of the femur and a 46% increase in stiffness, indicating quality bone formation. Thus the new bone that is deposited it also of high quality.

The next step in this work would like to determine why this combination of a PGK promotor and PDGFB worked so well. Zhang and others have discovered that PDGFB promotes bone marrow mesenchymal stem cell formation and angiogenesis, which are two important factors in bone growth. They also found that optimizing the dosage of PDGFB is quite important for promoting osteoblast (bone-forming) cell formation.

Finally Zhang’s group investigated how osteoclastogenesis, or the creation of cells that reabsorb bone (osteoclasts) is affected by PDGFB with a PGK promotor. The treated femurs also had an increase in biomarkers for osteoclasts. This increase in both osteoblasts and osteoclasts indicates that the treated bones undergo the normal bone rebuilding and remodeling cycle.

Overall, this research provides a compelling investigational pathway for future cell therapies to treat osteoporosis. Mouse models show a fast-acting technique that result in bone formation and increasing bone strength.