HA4 (Hyaluronan 4 mers)

HA4 is produced through digesting high molecular weight hyaluronan around an unfertilized egg by hyaluronidase of sperm just before fertilization.

HA4 promotes the growth of fertilized eggs (totipotent stem cells).

HA4 promotes the differentiation of somatic stem cells while keeping stemness.

HA4 induces longevity genes, sirtuins.

Reports of HA4

HA4 bioactivity was reported by Asari et al. in 2002 for the first time. This article showed that HA4 enhanced stress protein expression and suppressed cell death under the stress condition that induces cell death [1]. 

In 2004, Asari et al. showed that rats with spinal cord injury treated with HA4 can walk at Gordon Conference Proteoglycans (invited speaker) [2]. This result was also reported by Nagoya University [3] and Peking University [4].

In 2013, Sherman and Asari et al. showed that HA4 suppresses the progression of multiple sclerosis [5].

In 2014, Asari and Hascallet al. showed that HA4 induced longevity gene (sirtuins) expression, promoted hyaluronan production and stem cell proliferation/differentiation in rat epidermis in Gordon Conference Proteoglycans [6] and Gordon Conference Cornea [7].

In 2016, Sunabori and Asari et al. reported that HA4 suppresses neuronal cell death and glial scar formation in cerebral ischemia models [8].

REFERENCES

1. Effect of hyaluronan oligosaccharides on the expression of heat shock protein 72. Xu H, Ito T, Tawada A, Maeda H, Yamanokuchi H, Isahara K, Yoshida K, Uchiyama Y, Asari A. J Biol Chem.2002 10;277(19):17308-14.
   
2. Effects of hyaluronan tetrasaccharides on spinal cord injury. Gordon Research Conference Proteoglycans 2004. Invited speaker.
3. Hyaluronan oligosaccharides promote functional recovery after spinal cord injury in rats. Wakao N, Imagama S, Zhang H, Tauchi R, Muramoto A, Natori T, Takeshita S, Ishiguro N, Matsuyama Y, Kadomatsu K. Neurosci Lett. 2011 Jan25;488(3):299-304.
   
4. Hyaluronan tetrasaccharide exerts neuroprotective effect and promotes functional recovery after acute spinal cord injury in rats. Wang J, Wang X, Wei J, Wang M. Neurochem Res. 2015 Jan;40(1):98-108.
   
5. Hyaluronan oligosaccharides perturb lymphocyte slow rolling on brain vascular endothelial cells: implications for inflammatory demyelinating disease. Winkler CW, Foster SC, Itakura A, Matsumoto SG, Asari A, McCarty OJ, Sherman LS. Matrix Biol. 2013 Apr 24;32(3-4):160-8.
   
6. Hyaluronan Tetrasaccharides, HA4 Promotes Stemness and Sirtuin Expression. Gordon Research Conference, Proteoglycans, Diverse Regulators of Health and Disease. Akira Asari, Vincent C. Hascall. 6-11, 2014, Proctor Academy, Andover, NH. Invited speaker.
   
7. Effects of Hyaluronan Tetrasaccharides, HA4 on Stemness and Corneal Wound Healing. Akira Asari, Vincent C. Hascall. Gordon Research Conference, 
Cornea, Biology & Pathobiology of the Cell Lineage and Fate Determination on the Ocular Surface During 
Development and Disease. 16-21, 2014, Ventura Beach Marriott, Ventura, CA. Invited speaker.
8. Suppression of ischemia-induced hippocampal pyramidal neuron death by hyaluronan tetrasaccharide through Inhibition of Toll-Like Receptor 2 Signaling Pathway.Sunabori T, Koike M, Asari A, Oonuki Y, Uchiyama Y. Am J Pathol.2016 Aug;186(8):2143-51.