stem cells

[05survivor]

I know that we have not reached the point where human/clinical trials are happening. Yet, I was wondering has there been any literature on the benfit of using or trying to use the embillical cord for this purpose? I know that embryonic stem cells are the way to go, so to speak, but what about the embellical cord? Does the embellical cord contain the "right" type of stem cells to be used for trials? Any info appreciated.

[paolocipolla]

Survivor go here:

http://sci.rutgers.edu/forum/showthr...t=68259&page=2

Poast # 13 should help answer your question

[05survivor]

Thanks. Also, has anyone tried to use their "own"embillical cord, say from a pregnancy after SCI? Should you try to save the cord?

[dan#3]

my plan is to find a mad researcher to mix all different types to current self embryonic type that match best a combo anti regejction ,growth boost, netrulize inhibiters

[Wise Young]

Originally Posted by 05survivor

I know that we have not reached the point where human/clinical trials are happening. Yet, I was wondering has there been any literature on the benfit of using or trying to use the embillical cord for this purpose? I know that embryonic stem cells are the way to go, so to speak, but what about the embellical cord? Does the embellical cord contain the “right“ type of stem cells to be used for trials? Any info appreciated.

05survivor,

Several laboratories have reported that umbilical cord blood is beneficial in rats after spinal cord injury. Unfortunately, without clinical trials to show that the treatment is safe and effective, a number of clinics around the world have been giving human umbilical cord blood (HUCB) to people with spinal cord injury, telling them that it may cure them and charging them for the therapy. On the surface, it may seem reasonable to give people a chance to try this treatment that has been used to treat other conditions. Why not allow people to try the treatment?

The problem is that none of these places are carefully evaluating the patients before and after the treatment, nor are they comparing the recovery of treated patients against against patients who did not receive the treatment. Thus, despite several years of using umbilical cord blood in hundreds of patients, we currently do not know that umbilical cord blood cells have any benefit in humans. They are also not reporting complications that the patients are having and thus we don't know whether the treatment is safe.

One company that is treating patients with human umbilical cord blood is called Beike Biotechnology. Located in Shenzhen, this company gives human umbilical cord blood to people with many neurological diseases, ranging from spinal cord injury to amyotrophic lateral sclerosis. This is done in several hospitals in different parts of China. They are apparently charging patients $20,000-$30,000 for the treatment, hospitalization, and various other services that are being delivered.

The company will not divulge details of the treatment but, based on the information that people have described on this web site, they appear to be treating patients with CD34+ cells that are isolated and grown from fresh umbilical cord blood units. They inject the cells intravenously or intrathecally (into the cerebrospinal fluid surrounding the spinal cord). The cells are not HLA-antigen matched to the patients (which is normally done whenever umbilical cord blood is used) because the company believes that the cells are not rejected. They have claimed that the treatment is 100% safe and 80% effective.

I have been critical of Beike for three reasons. First, the company does not follow up the patients carefully and has never published any of its findings, other than to encourage the patients to report their impressions on a web site. Second, in my opinion, there is no evidence that the umbilical cord blood cells are immune privileged. Many years of using human umbilical cord blood for treating hematopoietic disorders indicate that cells that do not match at least 4/6 HLA antigens are usually rejected. Third, the company is providing what I consider to be misleading information concerning the efficacy and safety of the treatment for spinal cord injury.

There are several other clinics that are treating patients with spinal cord injury with human umbilical cord blood. For example, the Tijuana clinic that has long treated spinal cord injury patients with so-called shark embryos has now turned to transplanting human umbilical cord blood cells into patients with spinal cord injury. I don't know whether they use HLA-matched cells or not. I have heard that there is a center in Monterey, Mexico that apparently has transplanted umbilical cord blood cells to people with spinal cord injury. I have heard that there are also some places in the Caribbean.

All the above does not mean that umbilical cord blood cells are ineffective. The truth is that we don't know and these groups are taking advantage of desperate people, asking them to pay large sums for cells of unknown quality and efficacy, often without doing HLA-matching of the cells and through routes that are very unlikely to get the cells into the spinal cord. They make unsubstantiated claims for the efficacy and safety of the treatment. Worse, they are not following up the patients to assess the outcomes. In short, they are scamming people, using a promising source of cells but for which there is currently no credible data of efficacy for spinal cord injury.

So, what is known about umbilical cord blood cells and their effect on spinal cord injury? Let me review some of the key reports on this subject (the references and abstracts are listed at the end of this post):
• In 2004, Saporta, et al. reported that infusing human umbilical cord blood (hUCB) improve neurological recovery in rats that have had spinal cord injury from clip compression. They claim that the treatment apparently works when given as late as 5 days after spinal cord injury. To my knowledge, this study has never been replicated by any other laboratory.
• In 2004, Zhao, et al. transplanted human CD34+ cells into hemisected rat spinal cords and reported that rats treated with CD34+ cells achieved better improvement in functional scores than those that received bone marrows stromal cells. They report that BrdU-labeled CD34+ cells survived and migrated into the injury site. CD34 is generally thought to be a marker of hematopoietic stem cells. In our experience, human cells are immune-rejected by rat spinal cord, usually within 3-4 weeks. By the way, hemisected rats always recover walking. It is possible that the treatment enhanced recovery rate of the rats.
• In 2005, Kuh, et al. transplanted hUCB cells into the spinal cord of rats, using our spinal cord contusion model. In one treatment group, they gave a neurotrophic factor (BDNF) alongside the cells. They showed that the rats treated with hUCB and BDNF showed significantly better locomotor scores than those treated with hUCB alone or control untreated rats.
• In 2006, Nishio, et al. transplanted hUCB enriched for CD34+ cells in matrigel at one week after spinal cord contusion while they transplanted only matrigel in control rats. Immunohistological examination of the spinal cords revealed that human CD34+ cells survived for about 3 weeks and all were gone by 5 weeks after injury. The treated rats had smaller lesions and walked better.
• In 2007, Dasari, et al. published two papers on the subject. One reported the results of transplanting hUCB into spinal cord of rats at one week after spinal cord contusion. They found that the hUCB cells formed myelin around axons, survived at least two weeks, and claimed that he cells differentiated into neurons and oligodendroglia. They report that the treated rats walked better than controls. In the second paper, they report that hUCB reduces expression of FAS, an inflammatory cytokine that contributed to apoptosis or programmed cell death. They propose that this is the mechanism by which the hUCB may work in subacute spinal cord injury. In 2008, Dasari, et al. published a third paper in which they claimed that there were substantial number of surviving hUCB cells in injured spinal cord as long as 5 weeks after transplantation.
• In 2008, Kao, et al. reported that hUCB CD34+ cells attenuate spinal cord injury when transplanted into rat spinal cord that were compressed for 1 minute with an aneurysm clip. They report beneficial effects of the transplants and upregulation of VEGF and GDNF expression in the spinal cord, suggesting that the HUCB cells stimulated the production of these two growth factors and they may be responsible for the beneficial effects.

In summary, several independent laboratories have reported that hUCB cells are beneficial in rat spinal cord injury models. The initial studies by Saporta, et al. and Zhao, et al. are significantly flawed and left many unanswered questions. However, the subsequent studies by Kuh, Nishio, and Dasari, et al. are more credible. In these studies, cells were transplanted a week after contusion injury. Since all three groups used our spinal cord injury model and I trained people in the laboratories, I have greater confidence in the injuries and outcome measures. Basically the three studies (in Korea, Japan, and the USA) reported that transplanted hUCB cells survive only several weeks. None of the groups used immunosuppression to prevent rejection of the cells. Xenografts (cross-species, e.g. human to rat) into the spinal cord usually survive for 3-4 weeks and are gone by 5 weeks. I am not convinced that any of the groups showed that the transplanted cells themselves produced neurons or myelinating cells. Two of the groups reported that hUCB cell transplants alone improved locomotor recovery. One group reported better recovery only with hUCB plus BDNF. Dasari, et al. reported in 2008 that cells survived in the spinal cord for up to 5 weeks. They, however, used BrdU labelling of cells which can give misleading impressions of surviving cells.

In any case, I believe that it is important to carry out rigorous clinical trials to assess the risk and benefits of human umbilical cord blood cells transplants in people. Hundreds of patients are now receiving these treatments around the world. We are currently organizing clinical trials in China to test the effects of umbilical cord blood cells. We are focusing on people with chronic spinal cord injury (>1 year and stable neurological function for at least 6 months). We will use HLA-matched hUCB cells (to reduce rejection), transplant the cells directly into the spinal cord, and carefully assess the recovery of people for a year afterward. Recently, we found that lithium stimulates hUCB cells to produce neurotrophins. We have consequently proposed to combine lithium and HLA-matched hUCB cell transplantation.

One unanswered question is whether we should use mononuclear cells or CD34+ cells. While some investigators have used CD34+ enriched hUCB cells, others have used just hUCB mononuclear cells. Mononuclear cells include all the stem cells in the cord blood. About 2% of mononuclear cells are CD34+. CD34 is believed to be a marker of hematopoietic stem cells but this is controversial. Lithium stimulates mononuclear cells to produce neurotrophins, not necessarily CD34+. In any case, since we don't know whether the beneficial effect is coming from CD34+ cells or other mononuclear cells, we decided to start with mononuclear cells.

We have organized the ChinaSCiNet to carry out the trials. The phase 1 and 2 lithium trials have started, assessing the safety and efficacy of lithium alone. We will be submitting the application for the phase 2 trial to assess HLA-mached hUCB cell transplants in people with chronic spinal cord injury, to find out the best and safest cell dose to use. In 2009, depending on the results of the phase 2 hUCB transplant trial, we hope to initiate the phase 3 hUCB plus lithium trial, testing the combination of hUCB mononuclear cells and lithium In clinical trial, where all the patients would get the transplant and half would get lithium in addition. If the hUCB alone or with lithium is not beneficial in restoring function, we can say that the treatment is ineffective and recommend against its use. If hUCB plus lithium is effective, i.e. improves function compared to pre-treatment and compared to hUCB alone, then we can recommend the use of hUCB plus lithium. If hUCB transplantation is effective both with and without lithium, we would need to do a further clinical trial to confirm that the treatment effect is not due to the transplantation procedure alone.

We are currently raising funds to initiate similar trials In the U.S.

Wise.




References Cited

• Saporta S, Kim JJ, Willing AE, Fu ES, Davis CD and Sanberg PR (2003). Human umbilical cord blood stem cells infusion in spinal cord injury: engraftment and beneficial influence on behavior. J Hematother Stem Cell Res. 12: 271-8. Center for Aging and Brain Repair and Department of Anatomy, University of South Florida College of Medicine, Tampa, FL 33612, USA. ssaporta@hsc.usf.edu. The use of human umbilical cord blood (hUCB)--a rich source of nonembryonic or adult stem cells--has recently been reported to ameliorate behavioral consequences of stroke. In this study, we tested whether human cord blood leukocytes also ameliorate behavioral impairments of spinal cord injury. Rats were divided into five groups: (1) laminectomy (without spinal cord injury) only; (2) laminectomy + cord blood infusion; (3) spinal cord injury + cord blood infused 1 day post injury; (4) spinal cord injury + cord blood infused 5 days post injury; and (5) spinal cord injury only. Spinal cord injury was induced by compressing the spinal cord for 1 min with an aneurysm clip calibrated to a closing pressure of 55 g. Open-field behavior was assessed 1, 2, and 3 weeks after intravenous injection of prelabeled human cord blood cells. Open-field test scores of spinal cord injured rats treated with human cord blood at 5 days were significantly improved as compared to scores of rats similarly injured but treated at day 1 as well as the otherwise untreated injured group. The results suggest that cord blood stem cells are beneficial in reversing the behavioral effects of spinal cord injury, even when infused 5 days after injury. Human cord blood-derived cells were observed in injured areas, but not in noninjured areas, of rat spinal cords, and were never seen in corresponding areas of spinal cord of noninjured animals. The results are consistent with the hypothesis that cord blood-derived stem cells migrate to and participate in the healing of neurological defects caused by traumatic assault.
  
• Zhao ZM, Li HJ, Liu HY, Lu SH, Yang RC, Zhang QJ and Han ZC (2004). Intraspinal transplantation of CD34+ human umbilical cord blood cells after spinal cord hemisection injury improves functional recovery in adult rats. Cell Transplant. 13: 113-22. National Research Center for Stem Cell Engineering & Technology, State Key Laboratory of Experimental Hematology, Institute of Hematology, Chinese Academy of Medical Sciences, Peking Union Medical College, Tianjin, People's Republic of China. The present study was designed to compare the functional outcome of the intraspinal transplantation of CD34+ human umbilical cord blood (CB) cells with that of human bone marrow stromal (BMS) cells in adult rats with spinal cord injury. Sixty adult Wistar rats were subjected to left spinal cord hemisection, and then divided into three groups randomly. The control group received an injection of PBS without cells, while the two other groups of rats received a transplantation of 5 x 10(5) CD34+ CB or BMS cells, respectively. Functional outcome was measured using the modified Tarlov score at days 1, 7, 14, 21, and 28 after transplantation. A statistically significant improvement in functional outcome and survival rate in the experimental groups of rats was observed compared with the control group. Rats that received CD34+ CB cells achieved a better improvement in functional score than those that received BMS cells at days 7 and 14 after transplantation. Histological evaluation revealed that bromodeoxyuridine (BrdU)-labeled CD34+ CB and BMS cells survived and migrated into the injured area. Some of these cells expressed glial fibriliary acidic protein (GFAP) or neuronal nuclear antigen (NeuN). Our data demonstrate for the first time that intraspinal transplantation of human CD34+ CB cells provides benefit in function recovery after spinal cord hemisection in rats and suggest that CD34+ CB cells may be an excellent choice of cells as routine starting material of allogenic and autologous transplantations for the treatment of spinal cord injury.
  
• Kuh SU, Cho YE, Yoon DH, Kim KN and Ha Y (2005). Functional recovery after human umbilical cord blood cells transplantation with brain-derived neutrophic factor into the spinal cord injured rat. Acta Neurochir (Wien). 147: 985-92. Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Korea. There have been many efforts to recover neuronal function from spinal cord injuries, but there are some limitations in the treatment of spinal cord injuries.The neural stem cell has been noted for its pluripotency to differentiate into various neural cell types. The human umbilical cord blood cells (HUCBs) are more pluripotent and genetically flexible than bone marrow neural stem cells. The HUCBs could be more frequently used for spinal cord injury treatment in the future.Moderate degree spinal cord injured rats were classified into 3 subgroups, group A: media was injected into the cord injury site, group B: HUCBs were transplanted into the cord injury site, and group C: HUCBs with BDNF (Brain-derived neutrophic factor) were transplanted into the cord injury site. We checked the BBB scores to evaluate the functional recovery in each group at 8 weeks after transplantation. We then, finally checked the neural cell differentiation with double immunofluorescence staining, and we also analyzed the axonal regeneration with retrograde labelling of brain stem neurons by using fluorogold. The HUCBs transplanted group improved, more than the control group at every week after transplantation, and also, the BDNF enabled an improvement of the BBB locomotion scores since the 1 week after its application (P<0.05). 8 weeks after transplantation, the HUCBs with BDNF transplanted group had more greatly improved BBB scores, than the other groups (P<0.001). The transplanted HUCBs were differentiated into various neural cells, which were confirmed by double immunoflorescence staining of BrdU and GFAP & MAP-2 staining. The HUCBs and BDNF each have individual positive effects on axonal regeneration. The HUCBs can differentiate into neural cells and induce motor function improvement in the cord injured rat models. Especially, the BDNF has effectiveness for neurological function improvement due to axonal regeneration in the early cord injury stage. Thus the HUCBs and BDNF have recovery effects of a moderate degree for cord injured rats.
  
• Nishio Y, Koda M, Kamada T, Someya Y, Yoshinaga K, Okada S, Harada H, Okawa A, Moriya H and Yamazaki M (2006). The use of hemopoietic stem cells derived from human umbilical cord blood to promote restoration of spinal cord tissue and recovery of hindlimb function in adult rats. J Neurosurg Spine. 5: 424-33. Department of Orthopaedic Surgery, Chiba University Graduate School of dicine, Tougane Chiba Prefecture Hospital, Chiba, Japan. OBJECT: The use of human umbilical cord blood (HUCB) cells has been reported to improve functional recovery in cases of central nervous system injuries such as stroke, traumatic brain injury, and spinal cord injury (SCI). The authors investigated the effects of hemopoietic stem cells that were derived from HUCB and transplanted into the injured spinal cords of rats. METHODS: One week after injury, an HUCB fraction enriched in CD34-positive cells was transplanted into the experimental group. In control animals, vehicle (Matrigel) was transplanted. Recovery of motor functions was assessed using the Basso-Beattie-Bresnahan Locomotor Scale, and immunohistochemical examinations were performed. Cells from HUCB that were CD34 positive improved functional recovery, reduced the area of the cystic cavity at the site of injury, increased the volume of residual white matter, and promoted the regeneration or sparing of axons in the injured spinal cord. Immunohistochemical examination revealed that transplanted CD34-positive cells survived in the host spinal cord for at least 3 weeks after transplantation but had disappeared by 5 weeks. The transplanted cells were not positive for neural markers, but they were positive for hemopoietic markers. There was no evidence of an immune reaction at the site of injury in either group. CONCLUSIONS: These results suggest that transplantation of a CD34-positive fraction from HUCB may have therapeutic effects for SCI. The results of this study provide important preclinical data regarding HUCB stem cell-based therapy for SCI.
  
• Dasari VR, Spomar DG, Gondi CS, Sloffer CA, Saving KL, Gujrati M, Rao JS and Dinh DH (2007). Axonal remyelination by cord blood stem cells after spinal cord injury. J Neurotrauma. 24: 391-410. Program of Cancer Biology, Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, Illinois 61605, USA. Human umbilical cord blood stem cells (hUCB) hold great promise for therapeutic repair after spinal cord injury (SCI). Here, we present our preliminary investigations on axonal remyelination of injured spinal cord by transplanted hUCB. Adult male rats were subjected to moderate SCI using NYU Impactor, and hUCB were grafted into the site of injury one week after SCI. Immunohistochemical data provides evidence of differentiation of hUCB into several neural phenotypes including neurons, oligodendrocytes and astrocytes. Ultrastructural analysis of axons reveals that hUCB form morphologically normal appearing myelin sheaths around axons in the injured areas of spinal cord. Colocalization studies prove that oligodendrocytes derived from hUCB secrete neurotrophic hormones neurotrophin-3 (NT3) and brain-derived neurotrophic factor (BDNF). Cord blood stem cells aid in the synthesis of myelin basic protein (MBP) and proteolipid protein (PLP) of myelin in the injured areas, thereby facilitating the process of remyelination. Elevated levels of mRNA expression were observed for NT3, BDNF, MBP and PLP in hUCB-treated rats as revealed by fluorescent in situ hybridization (FISH) analysis. Recovery of hind limb locomotor function was also significantly enhanced in the hUCB-treated rats based on Basso-Beattie-Bresnahan (BBB) scores assessed 14 days after transplantation. These findings demonstrate that hUCB, when transplanted into the spinal cord 7 days after weight-drop injury, survive for at least 2 weeks, differentiate into oligodendrocytes and neurons, and enable improved locomotor function. Therefore, hUCB facilitate functional recovery after moderate SCI and may prove to be a useful therapeutic strategy to repair the injured spinal cord.
  
• Dasari VR, Spomar DG, Li L, Gujrati M, Rao JS and Dinh DH (2007). Umbilical Cord Blood Stem Cell Mediated Downregulation of Fas Improves Functional Recovery of Rats after Spinal Cord Injury. Neurochem Res. Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, Peoria, IL, 61656, USA. Human umbilical cord blood stem cells (hUCB), due to their primitive nature and ability to develop into nonhematopoietic cells of various tissue lineages, represent a potentially useful source for cell-based therapies after spinal cord injury (SCI). To evaluate their therapeutic potential, hUCB were stereotactically transplanted into the injury epicenter, one week after SCI in rats. Our results show the presence of a substantial number of surviving hUCB in the injured spinal cord up to five weeks after transplantation. Three weeks after SCI, apoptotic cells were found especially in the dorsal white matter and gray matter, which are positive for both neuron and oligodendrocyte markers. Expression of Fas on both neurons and oligodendrocytes was efficiently downregulated by hUCB. This ultimately resulted in downregulation of caspase-3 extrinsic pathway proteins involving increased expression of FLIP, XIAP and inhibition of PARP cleavage. In hUCB-treated rats, the PI3K/Akt pathway was also involved in antiapoptotic actions. Further, structural integrity of the cytoskeletal proteins alpha-tubulin, MAP2A&2B and NF-200 has been preserved in hUCB treatments. The behavioral scores of hind limbs of hUCB-treated rats improved significantly than those of the injured group, showing functional recovery. Taken together, our results indicate that hUCB-mediated downregulation of Fas and caspases leads to functional recovery of hind limbs of rats after SCI.
  
• Dasari VR, Spomar DG, Li L, Gujrati M, Rao JS and Dinh DH (2008). Umbilical cord blood stem cell mediated downregulation of fas improves functional recovery of rats after spinal cord injury. Neurochem Res. 33: 134-49. Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, Peoria, IL, 61656, USA. Human umbilical cord blood stem cells (hUCB), due to their primitive nature and ability to develop into nonhematopoietic cells of various tissue lineages, represent a potentially useful source for cell-based therapies after spinal cord injury (SCI). To evaluate their therapeutic potential, hUCB were stereotactically transplanted into the injury epicenter, one week after SCI in rats. Our results show the presence of a substantial number of surviving hUCB in the injured spinal cord up to five weeks after transplantation. Three weeks after SCI, apoptotic cells were found especially in the dorsal white matter and gray matter, which are positive for both neuron and oligodendrocyte markers. Expression of Fas on both neurons and oligodendrocytes was efficiently downregulated by hUCB. This ultimately resulted in downregulation of caspase-3 extrinsic pathway proteins involving increased expression of FLIP, XIAP and inhibition of PARP cleavage. In hUCB-treated rats, the PI3K/Akt pathway was also involved in antiapoptotic actions. Further, structural integrity of the cytoskeletal proteins alpha-tubulin, MAP2A&2B and NF-200 has been preserved in hUCB treatments. The behavioral scores of hind limbs of hUCB-treated rats improved significantly than those of the injured group, showing functional recovery. Taken together, our results indicate that hUCB-mediated downregulation of Fas and caspases leads to functional recovery of hind limbs of rats after SCI.

[05survivor]

Thank you Dr. Young for your response and info. I take it that there has not been an incidence where women use their own embillical cord for the stem cell extracts?

[Wise Young]

Originally Posted by 05survivor

Thank you Dr. Young for your response and info. I take it that there has not been an incidence where women use their own embillical cord for the stem cell extracts?

The umbilical cord blood is the baby's blood, not the mother's. It has a good chance of a match but no guaranteed. Nope, I don't know of any woman who has been treated the umbilical cord blood of her child.

Wise.

[05survivor]

Thank you for the response and clarification Dr. Young.

[Jason C]

And as of right now there is no proof that these treatments work at all.There have always been people willing to take advantage of those who are looking for hope wherever they can find it. The biggest mistake, as Dr. Young has often said, is having the attitude that you have "nothing to lose". First of all there's the money. Money is clearly not everything and a cure would be invaluable, but you'd be paying a ton of cash for something that might not even work. Then there's the fact that you're letting someone inject "something" into you. What is it, really? You have no way of knowing for sure. Look at the medical standards in some of the countries where these treatments are taking place. You have a lot to lose. Depending on what is actually being put into your body and whether or not the doctor even knows how to properly execute the procedure, you could end up in an even worse state of health than you started. Doing research is definitely a good thing. More people should be wary of these experimental "treatments". I mean, they're not EVEN a clinical trial and they want YOU to pay THEM?? Your money would be far better spent if you donated it to legitimate researchers who are actually logging data and looking for actual effective treatments.

In America it's the drug companies that scare me. Let me rephrase that: it's our ATTITUDE toward drugs that scares me. I think many of us put too much faith in anyone who happens to be wearing a white lab coat. Once upon a time clinical drug trials used to seem like a fairly risky thing. These research companies would pay people quite a bit of money to participate in their experiments. Now I see commercials on TV all the time advertising these same types of trials and making a big deal about getting "free drugs!". Like you should be thanking them for putting experimental chemicals in your body. Like they're doing YOU a favor instead of the other way around. Ahh but I'm off on a tangent now... anyway...

Keep doing research, keep your skeptisicm, and, most of all, keep your hope. Some truly amazing, legitimate research is being done right now.