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Recombinant Human Activin-A: Scientific background and Collaboration Opportunity

Scientific background
Activin A is a member of the TGF-β family that exhibits a wide range of biological activities including regulation of cellular proliferation and differentiation, and promotion of neuronal survival. Elevated levels of Activin A in human colorectal tumors and in post-menopausal woman have been implicated in colorectal and breast cancers, respectively. The biological activities of Activin A can be neutralized by inhibins and by the diffusible TGF-β antagonist, Follistatin. Human Activin A is a 26.0 kDa disulfide-linked homodimer of two βA chains (connected by a sulfide bond), each containing 116 amino acid residues.

Therapeutic Potential: Stem Cell Differentiation
Some of the most promising research involving Activin A has been examining how the addition of Activin A in combination with other cytokines and growth factors differentiates stem cells into diverse, mature cells. Other than the different combinations of growth factors influencing the differentiation of stem cells, Activin A also can differentiate stem cells into different mature cells based on when the Activin A is introduced to the stem cells as well as the total time the stem cells are present with Activin A. One example is how Activin A, in combination with BMP4, TGF-Beta 3, and Wnt3a, differentiates embryonic stem cells (ESCs) into cartilage. The ESCs underwent chondrogenic induction and the long term supplementation of the cells with Activin A promoted articular cartilage formation.1 A different group has noticed that hESCs can be differentiated towards endoderm cells with an increase in Activin A concentration as compared to BMP4 and VEGF levels. The three cytokines each drove the ESCs to differentiate into different cells.2
            Another research institute has uncovered that mESCs can be differentiated into Noto-expressing cells (Notochord-like Cells) when using Activin A. This process is further aided with the inhibition of BMP and Wnt.3 Activin A can also be added to definitive endoderm (DE) cells to induce them to differentiate into hepatic or pancreatic progenitor cells. The Activin A mediates the Nodal signaling pathway. The researchers found that Activin A in combination with LiCl activation of the Wht pathway results in a greater efficiency of generating ES cell-derived DE cells.4
            Other researchers have discovered that gnotobiotic porcine skin-derived stem cells (gSDSCs) treated with Activin A, glucagon-like peptide 1 (GLP-1), and nicotinamide results in the generation of insulin-producing cells. The gSDSCs expressed insulin and had increased insulin synthesis after glucose stimulation.5 Activin A is also required for the chondrogenic and osteogenic differentiation of mesenchymal progenitor cells (MPCs). Both the Activin A levels as well as the Activin A to Follistatin ratio influence the differentiation of the MPCs. Moreover, Activin A inhibits the adipogenesis of MPCs.6

Therapeutic Potential: Cancer
The role of Activin A in the development of cancers has also been studied. Activin A has been shown to both inhibit as well as promote different types of cancer. Some of the early research showed that Activin A inhibited the proliferation of human tumor cells. One group discovered that Activin A inhibits the cell growth cycle of human breast cancer cells, stopping the cycle in the G stage7, through the p38 MAPK pathway.8 Other researchers have found that Activin A inhibits the proliferation of human colon cancer RKO cells via expression of SLC5A8 expression through the Smad3 signaling pathway.9 Activin A has also been shown to inhibit cell growth in other human cells, such as prostate cancer, breast, leukemia vascular endothelial, fetal adrenal, and vascular smooth muscle cells. However, the mechanisms in all these examples have not been the same.10

However, Activin A also plays a role in cancer proliferation. In one study elevated levels of Activin A were observed in glioblastoma cells compared to normal brain tissue. The over expression of Activin A produced a dose-dependent increase in DNA synthesis of U87 glioblastoma cells and enhanced the cancer proliferation.11

Activin A has also been shown to promote multiple myeloma (MM). In this case MM enhances Activin A secretion by marrow stromal cells, which then inhibited osteoblast differentiation and aided in creating an environment that favors osteolysis. Targeting the Activin A reversed the osteoblast inhibition and inhibited the tumor growth in in-vivo humanized MM models.12 Another research group found out that treatment of osteoblast-like cells results in cells shifting towards the G1 phase of the cell cycle and an overall decrease of cell death. The cells had no increase in proliferation, which confirmed that the only source of the additional cells was the reduced cell death rate.13

Therapeutic Potential: Reproductive
Activin A has also been found to performance a large role in the reproductive system. One example is the critical role Activin A has in male mice fertility. Activin A level raises in the testis but not the ovary after sex determination (embryonic day 12.5). Mice without Activin A have smaller testes and lower Sertoli cell number. Moreover, Activin A dosage contributes to the balance between Sertoli and germ cell numbers that is required for male fertility.14 Additional research has uncovered that Activin A, which is a product of fetal Leydig cells, is required for fetal testis development as well.15

A research group from Australia has observed that Activin A also has negative adhesive properties, which cause implantation failure. Activin A causes a decrease in cell adhesion molecules (CAM) production, which contributes to implantation failure. The research group believes that this effect might explain the infertility observed in women with endometriosis-associated infertility.16 Another research group has detected that serum Activin A levels are elevated in patients with preeclampsia as compared with normal controls. The researchers also found that Inhibin A levels were elevated in the women with preeclampsia as well as a decrease in the level of PIGF. These three serum markers could be used to predict preeclampsia.17

Serum Activin A levels, however, are lower in ectopic pregnancies (EP) as compared to normal, intrauterine pregnancies. This information can be used to signal the presence of EP.18 Another group has discovered that the use of progesterone, VEGF, and Inhibin A as well as Activin A as four markers are better at distinguishing EP from normal pregnancies.19 Other research has uncovered that Activin A inhibits the activation of human primordial follicles in vitro. The effect is dose dependent and is related to the fact that Activin A promotes ganulosa cell proliferation in a dose dependent manner.20

Therapeutic Potential: Other
Activin A’s role in other diseases and conditions has also been studied in great detail. Just like other TGF superfamily members, Activin A has many roles throughout the body. The wide array of effects Activin A has range from helping to harming normal survival requirements. Some research concerning the role of Activin A and bone formation have discovered that inhibition of Activin A is good for bone formation. The inhibition of Activin A signaling has no effect on secondary growths and no change in cell proliferation of cancer. However, it does stimulate bone formation and prevents cancer-induced bone damage.21

Another group has examined the role of Activin A during inflammation. They have discovered that neutrophils are a significant source of Activin A. Moreover, TNF-a contributes to the circulation of Activin A during acute inflammation. Neutrophils secreted Activin A when stimulated by TNF-a within an hour while Activin mRNA expression did not increase until the twelfth hour of culture.22

The levels of serum Activin A were also examined in a few different rheumatic diseases. The researchers observed that in rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and osteoarthritis (OA) serum Activin A levels were higher compared to a control group. The RA and SLE levels were also significantly higher than the OA level and there was some positive correlation between the serum Activin A levels and the disease activity of both RA and SLE.23

Activin A also influences the number of mature beta cells in the pancreas. Researchers found that Activin A decreases the number of mature beta cells as well as decreasing the expression of insulin. There was an increase in the number of immature beta cells. Moreover, Activin A treated cells proliferated faster. Also, the researchers observed that all the Activin A effects were reversed by the addition of exogenous follistatin.24

Activin A also has a role in asthma. Researchers believe that blocking Activin A can be a treatment for asthma. Blocking Activin A with an antibody prevents the increase of IL-25 in the lung, which limits the enhanced airway hyper-reactivity and remodeling as well as inhibited collagen deposition.25

Other researchers have determined that Activin A activates the ALK4-Smad pathway in systemic sclerosis (SSc). For a long time, it was believed that TGF-b is responsible for inducing fibrosis. However, this study shows that Activin A also induces fibrosis in patients with SSc. Serum Activin A levels are higher in the patients with SSc compared to normal controls. Moreover, both Activin A and Activin receptor type 1B expression are higher in cultured SSc. Activin A induces the production of collagen. The researchers believe that inhibition of the Activin A - ALK4 - Smad pathway may be a new treatment of SSc.26

Activin A also has a potential role in the future of liver transplants. In rats, fetal liver stem / progenitor cells (FLSPCs) were used to repopulate livers of normal recipients. The older rats were repopulated 4-5 fold compared to the younger rats. Activin A inhibited proliferation of adult hepatocytes. Older rats, which possess less Activin receptors, had a built in resistance to Activin A, which resulted in FLSPCs repopulating the livers of older rats. Therefore, the limited proliferation of hepatocytes in older rats combined with increased apoptosis in older rats resulted in better transplant results and can potentially change transplantation strategies.27

Another group of researchers have ascertained that the mechanism of Activin A in neuron cells is different than the usual Smad pathway. Activin A promotes neuronal differentiation independent of Smad while using Activin type 1R. Therefore, Activin A can support neuronal survival in vitro.28

An additional role of Activin A is the proliferation and differentiation of human adipose progenitors. Researchers have uncovered that Activin A regulates the number of undifferentiated progenitors. Moreover, Activin A is expressed at higher levels in adipose tissue of obese patients compared to lean subjects.29

One more place that Activin A impacts the body is in the heart. Researchers have utilized a sheep model to discover that Activin A is released during cardiopulmonary bypass (CPB). The Activin A is biologically active and at higher levels than seen from surgery alone. The researchers believe that Activin A is associated with the adverse outcomes associated with systemic inflammation in cardiac surgery.30 Other researchers believe that Activin A can be used as a biomarker for Carcinoid heart disease (CHD). Activin A levels are elevated to the same degree for both early and advanced CHD. Moreover, the research shows that Activin A is an independent predictor of CHD.31

Another group of researchers demonstrated that Activin A is an important player in inflammation, repair and cytoprotection in various organs and can enhances the speed of wound healing and suggested to consider the use of Activin A for neuroprotection applications.32

Anti-Activin A in clinical trial
As of June 2011, Acceleron Pharma and Celgene Corp. are conducting Phase 2/3 clinical study of ACE-011 (sotatercept) for the treatment of chemotherapy-induced anemia (CIA) in patients with metastatic non-small cell lung cancer (NSCLC). ACE-011 is a soluble receptor fusion protein and bind with high affinity to Activin A.

Collaboration Opportunity
SBH Sciences Recombinant human Activin A is a soluble 26 kDa homodimeric protein consisting of two 116 amino acid residues which corresponds to the amino acid residues 311 – 426 of the full-length Activin A.

The biological activities of Activin-A can be neutralized by inhibins and by the diffusible TGF-beta antagonist, Follistatin.
The protein is produce by Insect cells (Hi5). The In-Vitro activity of the recombinant protein is measured based on its ability to inhibit the proliferation of murine MPC-11 cells.

SBH Sciences is looking for partners to investigate SBH Sciences recombinant Activin A as therapeutic agent, as well as diagnostic tool. Moreover, availability of our extensive bioassay support and the highly pure protein will also support project that aim to produce anti-Activin A (e.g., small drug-like substance or monoclonal antibodies).

We are open for suggestions and would be pleased to hear from you.

References:
1. Waese EY et al, Stem Cell Research, 6(1) 34-49, Jan 2011.

2. Outten JT et al, Stem Cell Research, 6(2) 129-42, Mar 2011.

*3. Winzi M et al, Stem Cells And Development, Feb 2011.

4. Li F et al, Journal Of Cellular Biochemistry, 112(4) 1022-34, Apr 2011.

5. Yang JH et al, Biochemical And Biophysical Research Communications, 397(4) 679-84, Jul 2010.

6. Djouad F et al, Stem Cell Research & Therapy, 1(2) 11, May 2010.

7. Burdette JE et al, Cancer Research, 65(17) 7968-75, Sep 2005.

8. Cocolakis E et al, The Journal Of Biological Chemistry, 276(21) 18430-6, May 2001.

9. Zhang Y et al, The International Journal Of Biochemistry & Cell Biology, 42(12) 1964-72, Dec 2010.

10. Chen YG et al, Experimental Biology And Medicine (Maywood, NJ), 227(2) 75-87, Feb 2002.

11. Zhang DF et al, The Journal Of International Medical Research, 38(4) 1343-53, Jul-Aug 2010.

12. Vallet S et al, Proceedings Of The National Academy Of Sciences Of The United States Of America, 107(11) 5124-9, Mar 2010.

13. Rosenberg N et al, Experimental And Clinical Endocrinology & Diabetes, 118(10) 708-12, Nov 2010.

14. Mendis SH et al, Biology Of Reproduction, 84(2) 379-91, Feb 2011.

15. Archambeault DR et al, Proceedings Of The National Academy Of Sciences Of The United States Of America, 107(23) 10526-31, Jun 2010.

16. Stoikos CJ et al, Human Reproduction, 25(7) 1767-74, Jul 2010.

17. Yu J et al, Ultrasound In Obstetrics & Gynecology, 37(5) 528-33, May 2011.

18. Florio P et al, Gynecological Endocrinology, 27(6) 391-5, Jun 2011.

19. Rausch ME et al, Obstetrics And Gynecology, 117(3) 573-82, Mar 2011.

20. Ding CC et al, Journal Of Assisted Reproduction And Genetics, 27(4) 141-7, Apr 2010.

21. Chantry AD et al, Journal Of Bone And Mineral Research, 25 (12) 2357-70, Dec 2010.

*22. Chen Y et al, Immunology And Cell Biology, Mar 2011.

23. El-Gendi SS et al, International Journal Of Rheumatic Diseases, 13(3) 273-9, Aug 2010.

24. Szabat M et al, Diabetologia, 53(8) 1680-9, Aug 2010.

25. Gregory LG et al, American Journal Of Respiratory And Critical Care Medicine, 182(2) 143-54, Jul 2010.

26. Takagi K et al, Journal Of Autoimmunity, 36(3-4) 181-8, May 2011.

27. Menthena A et al, Gastroenterology, 140(3) 1009-1020, Mar 2011.

28. Suzuki K et al, Biochemical And Biophysical Research Communications, 394(3) 639-45, Apr 2010.

29. Zaragosi et al, Diabetes, 59(10) 2513-21, Oct 2010.

30. Chen Y et al, Cytokine, 54(2) 154-60, May 2011.

*31. Bergestuen et al, Neuroendocrinology, 92(3) 168-77, 2010.

32. Sulyok S et al, Mol Cell Endocrinology, 15;225 (1-2): 127-32, Oct 2004.





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